Insulin-dependent Diabetes Mellitus Subjects Research Articles

Prospective evaluation of β-cell function in insulin antoantibody-positive relatives of insulin-dependent diabetic patients

During the preclinical period of insulin-dependent diabetes mellitus (IDDM), progression to clinical IDDM is characterized by declining β-cell function. Although the presence of insulin autoantibodies (IAA) improves the ability of islet cell antibodies (ICA) to predict subsequent clinical IDDM, few studies have examined the risk of developing IDDM in subjects positive for IAA but negative for both ICA and antibodies to glutamic acid decarboxylase (64kA). To investigate this question, detailed β-cell function tests (acute insulin response to glucose [AIR gluc] and slope of glucose potentiation) were performed on eight IAA-positive first-degree relatives of insulin-dependent diabetics. All eight subjects were negative for ICA, and seven were tested for 64kA and were negative. Five subjects were studied prospectively for 22.4 ± 9.4 months, while three subjects had only initial studies. Initial β-cell function tests were normal in each subject. AIR gluc was 122.2% ± 19.0% of the expected normal response, while slope was 168.6% ± 20.6% of expected normal response. β-cell function remained normal and remarkably stable in the five subjects followed prospectively. AIR gluc did not significantly change from an initial value of 147.9% ± 23.1% of expected to 153.2% ± 22.4% (NS). The slope of glucose potentiation varied little from 165.5% ± 39.4% initially to 159.5% ± 27.3% (NS) at the most recent determination. We conclude that among nondiabetic first-degree relatives of IDDM subjects, the presence of IAA in the absence of ICA and 64kA is not usually associated with and therefore does not reliably predict β-cell dysfunction or progressive deterioration in β-cell function.

The roles of insulin and catecholamines in the glucoregulatory response during intense exercise and early recovery in insulin-dependent diabetic and control subjects.

Intense exercise is associated with a marked stimulation of glucose production (Ra), a somewhat smaller increment in its utilization (Rd) (and therefore hyperglycemia), large increases in plasma catecholamines, and moderate hyperglucagonemia. The hyperglycemia increases in recovery and is accompanied by hyperinsulinemia. Because these adaptations are unique to intense exercise, we tested the physiological significance of the hyperinsulinemia by exercising six fit, postabsorptive young male subjects with insulin-dependent diabetes mellitus (IDDM) after overnight glycemic normalization by iv insulin, keeping its infusion rate constant during and for 2 h after 100% maximum VO2 cycle ergometer exercise to exhaustion (12 min) (no postexercise hyperinsulinemia). Their responses were compared with those of matched control subjects studied on two separate occasions, once without intervention (physiological hyperinsulinemia, n = 6) and again with a 0.05 U/kg iv bolus at exhaustion (postexercise supraphysiological hyperinsulinemia, n = 5). In all three study protocols, Ra increased by 7-fold, and Rd by 4-fold at exhaustion, and Ra declined in early recovery at the same rates. Therefore, the early recovery hyperinsulinemia is not required to return Ra to preexercise levels, and excessive hyperinsulinemia does not accelerate this decline. We infer that the catecholamine increments and decrements are the prime regulators of Ra (correlations of Ra vs. norepinephrine or epinephrine, P < 0.001 in the three studies), with a smaller contribution from the concurrent hyperglucagonemia. Rd, in contrast, was significantly affected by insulin. In the IDDM subjects, Rd remained at the same rate as Ra through most of recovery, resulting in sustained hyperglycemia and decreased glucose MCR, vs. the control subjects. This hyperglycemia compensated for the abnormal MCR, such that Rd was comparable to that in the control subjects. With the insulin bolus, the Rd elevation was sustained longer compared to the study without bolus, resulting in mild hypoglycemia successfully counterregulated by an increase in Ra. Thus, the principal regulators of the marked exercise increase and rapid recovery decrease in Ra are probably the catecholamines. The postexercise hyperinsulinemia is required for the MCR response and to return plasma glucose concentrations to preexercise levels. Different therapeutic strategies are required in persons with IDDM undergoing strenuous vs. moderate exercise, because of their inability to generate the postexercise hyperinsulinemia.

HLA-DQB1 typing of north east Italian IDDM patients using amplified DNA, oligonucleotide probes and a rapid DNA-enzyme immunoassay (DEIA)

We report on HLA-DQB1 typing in IDDM patients of north east Italian region using an enzymatic method based on the detection of hybridization reaction between PCR amplified DNA from whole blood and allele specific oligonucleotides by an antibody directed against double stranded DNA (DNA-enzyme immunoassay or DEIA). The method is reliable, simple and sensitive as the classical radioactive method with the advantage of using a universal non radioactive detection reagent. Nineteen families, each including one subject with juvenile insulin-dependent diabetes mellitus (IDDM) were analyzed. A strong association between absence of an aspartic acid (Asp) in position 57 of DQB1β chain in homozygous conditions and susceptibility to IDDM was found. In contrast with some previous observations, however, no significant association was found between Asp/non-Asp heterozygous genotype and IDDM. No patients were found with an homozygous Asp/Asp genotype, known to be protective in caucasoid population. Of particular interest was the DQB1 alleli distribution in our population sample. The non-Asp allele most frequently found in IDDM subjects was the DQB1 0201 allele and this finding was statistically significant (Pc value <0.05, relative risk = 5.01). No significant association was found for any other allele including the DQB1 0302 (Pc value = not significant although with relative risk = 3.28) previously reported as the most frequent allele in IDDM caucasoid patients.

Evidence for Cigarette Smoking as a Major Risk Factor for Periodontitis

The role of smoking as a risk factor for periodontitis was assessed separately in diabetic and nondiabetic study groups. Subject listings stratified for age (19 to 40 years) and sex were obtained for subjects with insulin-dependent diabetes mellitus (IDDM) and nondiabetic subjects. For both the IDDM group (n = 132) and the nondiabetic group (n = 95), age and sex stratified samples were constructed by random selection of subjects from each subject listing. Patients were recruited by phone, examined, and their medical and dental histories obtained. Among nondiabetic subjects, the prevalence of periodontitis was markedly higher among current smokers compared with never smokers (P < or = 0.005) in both the 19 to 30 year-old (46% vs. 12%) and 31 to 40 year-old groups (88% vs. 33%). The subject mean percent of sites with gingival pocket depth > or = 4 mm was higher among current smokers than never smokers (P = 0.001) in the 19 to 30 (8.2% vs. 3.4%) and 31 to 40 (14.3% vs. 4.3%) age groups. The effects of smoking among IDDM subjects were similar to that observed in the nondiabetic population. There were no differences between current and never smokers in the proportion of sites positive for plaque. Attributable risk percents from prevalence data suggest that among nondiabetic subjects, a large proportion, perhaps as much as 51% of the periodontitis in the 19 to 30 year old group and 32% of the periodontitis in the 31 to 40 year old group, is associated with smoking.(ABSTRACT TRUNCATED AT 250 WORDS)

The ethnic distribution of antibodies to glutamic acid decarboxylase: Presence and levels in insulin-dependent diabetes mellitus in Europid and Asian subjects

Our objective was to ascertain the frequency of antibodies to glutamic acid decarboxylase (GAD) in Europids and four Asian ethnic groups with insulin-dependent diabetes mellitus (IDDM) to gain insight into why the prevalence and incidence of IDDM varies so widely among ethnic and/or geographically diverse population groups. The subjects in this study were Europid ( n = 49), Japanese ( n = 16), Thai ( n = 7), Korean ( n = 21), and Chinese ( n = 13) persons with IDDM with a duration ranging from 5 to 14 years. There were similar numbers of healthy controls matched for each ethnic group. A validated radioimmunoprecipitation assay used GAD from pig brain radiolabeled with 125I using chloramine T. Islet cell cytoplasmic antibodies measured by indirect immunofluorescence were expressed as Juvenile Diabetes Foundation units. The prevalence of antibodies to GAD, compared with Europids (63%), was much lower in all Asian populations with IDDM: Japanese (31%), Thai (29%), Korean (5%), and Chinese (27%). The mean level of antibodies to GAD, however, among diabetics from each population who gave a positive reaction, was similar. For all groups, the prevalence of antibodies to GAD was much higher than that of islet cell cytoplasmic antibodies. Almost all IDDM subjects positive for islet cell antibodies had antibodies to GAD, but the converse did not hold. A radioimmunoprecipitation assay for antibodies to GAD applied to serum from subjects with IDDM in various ethnic groups showed that Europids with IDDM had a much higher prevalence of such antibodies than did Asians. This held for all ethnic groups, and particularly Koreans. Thus, among different populations, there may be etiologic heterogeneity of IDDM. Alternatively, if an autoimmune process is generally operative, different pancreatic autoantigens are involved.

A 64 kDa antigen/glutamic acid decarboxylase (GAD) in fetal pig pro-islets: Co-precipitation with a 38 kDa protein and recognition by T cells in humans at risk for insulin-dependent diabetes

The development of insulin-dependent diabetes mellitus (IDDM) is associated with circulating antibodies to a pancreatic islet protein of MW 64,000 (64 kDa), reported to be glutamic acid decarboxylase (GAD). To investigate the antigenic properties of the 64 kDa antigen/GAD in IDDM we employed fetal pig pro-islets, a convenient source of islet antigens and an alternative to adult human islets for transplantation. Pro-islets contained a 64 kDa protein precipitated by antibodies in the sera of 9 14 (64%) at-risk IDDM, 12 33 (36%) recent-onset IDDM and 4 12 (33%) established IDDM patients and in 1 18 (5%) healthy control subjects. In addition, a 38 kDa protein was co-precipitated with the 64 kDa protein by 6 14 (43%) at-risk IDDM, 5 33 (12%) recent-onset IDDM, 1 12 (8%) established IDDM patient sera and 1 18 (5%) control subject serum. Both 64 kDa and 38 kDa antigens were specific to pro-islets; neither was detected in fetal pig thyrocytes, hepatocytes or splenocytes. The majority of the 64 kDa protein was co-precipitated with GAD enzymatic activity from pro-islets by either IDDM sera or a sheep anti-GAD serum. Previously, we showed that peripheral blood mononuclear cells (PBMC) from over half the subjects defined as being at risk for IDDM proliferate in response to fetal pig pro-islets. Proliferative responses of PBMC from pre-diabetic subjects to a crude extract of pro-islets were therefore measured before and after depletion of GAD by adsorption of the extract against GAD-1 monoclonal antibody. In 5 10 at-risk subjects, T cell stimulation indices were greater than the control mean+2 SD and decreased in four by > 50% after depletion of GAD. In summary, a 64 kDa protein with the properties of GAD is present in fetal pig pro-islets and is recognized by both antibodies and T cells in a significant proportion of subjects at risk for early IDDM. Some subjects with anti-64 kDa antibodies also have antibodies that co-precipitate a 38 kDa pro-islet protein. Prospective studies of T cell reactivity in at-risk IDDM subjects are required to delineate the role of GAD and other candidate autoantigens in the initiation and progression of β cell destruction.

Analysis by the polymerase chain reaction of histocompatibility leucocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus.

DNA sequence analysis of class II HLA from Caucasian and black patients with type 1 (insulin-dependent) diabetes mellitus has suggested that aspartic acid at position 57 (Asp 57) of the DQ beta chain provides protection against insulin-dependent diabetes mellitus (IDDM). In contrast, most Japanese patients with IDDM have Asp 57-positive alleles. To determine the reason for the differences and to localize the HLA-linked diabetogenic gene in Japanese, we studied the DQA1 and DQB1 genes of Japanese patients with IDDM and control subjects by the polymerase chain reaction in combination with restriction fragment length polymorphism analysis. Associations of DQA1*0301 and DQB1*0303 with IDDM were observed. DQA1*01 was associated negatively with IDDM. The HLA-DR9 haplotype, which is associated positively with IDDM in Japanese, was associated with DQA1*0301 and DQB1*0303, indicating that the Japanese DR9 haplotype is the same as that in caucasians but different from that in blacks. Of the loci on Japanese DR9 haplotypes, the DQA1*0301 allele showed the highest association with IDDM. DQB1*0303 was also positively associated with IDDM. Since DQB1*0303 is identical to DQB1*0302 except that it contains Asp 57, the data suggests that an Asp 57-positive allele confers susceptibility to IDDM when the whole molecule of the DQ beta chain is similar to other susceptible DQ beta chains. DQA1*0301 appears to be a marker of IDDM in all these populations: Japanese, caucasian, and black.

Glutamic acid decarboxylase autoantibodies in preclinical insulin-dependent diabetes.

Insulin-dependent diabetes mellitus (IDDM) is associated with serum antibodies that precipitate a 64-kDa pancreatic islet cell protein reported to be glutamic acid decarboxylase (GAD; glutamate decarboxylase, EC 4.1.1.15). Previously, antibodies to GAD were found in the rare neurological disorder stiff man syndrome. To demonstrate directly antibodies to GAD, enzymatically active GAD was first purified from fresh human cerebellum. Brain GAD activity was precipitated by noninhibitory antibodies in the sera of 16/26 (62%) subjects defined as having preclinical IDDM (islet cell antibody-positive first-degree relatives of a person with IDDM), 3/13 (23%) with recent-onset IDDM, and 3/3 with the stiff man syndrome. In addition, sera of 5/26 (19%) preclinical and 2/13 (15%) recent-onset IDDM subjects contained antibodies that precipitated GAD but inhibited its activity. Thus, overall, 21/26 (81%) preclinical and 5/13 (38%) recent-onset IDDM subjects had antibodies that precipitated GAD activity. Antibodies to GAD were not detected in sera from subjects with other autoimmune diseases (n = 29) or healthy controls (n = 14). GAD affinity-purified to homogeneity (specific activity, 58 units/mg) was specifically immunoprecipitated as a single 60-kDa species by the IDDM sera. In an ELISA incorporating whole mouse brain GAD captured by the GAD-6 monoclonal antibody the frequencies of GAD antibodies for all subject groups were indistinguishable from those found by precipitation of human brain enzymatic activity. We conclude that (i) GAD is an (auto)antigen in a majority of subjects operationally defined as having preclinical IDDM, (ii) pancreatic islet and brain GAD are likely to be cross-reactive, and (iii) the majority of GAD antibodies are directed away from the catalytic site of the brain enzyme. The lower frequency of GAD antibodies in recent-onset IDDM subjects indicates either that immunoreactivity is lost with near-total beta-cell destruction or that GAD antibodies denote a low risk of progression to clinical disease.

Effects of low-protein diets on protein metabolism in insulin-dependent diabetes mellitus patients with early nephropathy.

The dietary protein requirements of patients with insulin-dependent diabetes mellitus (IDDM) are unknown. We studied the metabolic adaptation of IDDM patients with early nephropathy to therapeutic, low-protein diets. Six patients were studied at baseline and following 1 and 12 weeks of consuming 0.6 g/kg-1 ideal body weight.day-1 protein. Outcome variables included quadriceps muscle strength, body composition, nitrogen balance, and estimates of whole body protein turnover using an infusion of L-[1-13C]leucine. All subjects experienced decreased muscle strength (6.6% decline in maximal torque, P = 0.05) and increased body fatness (11% increase in fat mass, P = 0.03) with no change in total body weight. This was accompanied by an initial 40% decrease in the rate of whole-body leucine oxidation after 1 week of dietary restriction which returned almost to baseline rates by 12 weeks (P less than 0.001, 1 week vs. 12 weeks). Nitrogen balance remained negative throughout the period of protein restriction. We conclude that IDDM subjects with early nephropathy experience protein undernutrition during the first 3 months of the dietary protein restriction currently recommended for the treatment of nephropathy. This may result, in part, from an inability to conserve essential amino acids from oxidative loss over the time period of the study.

Temporal variation in incidence of IDDM in Canterbury, New Zealand.

To establish the statistical significance of observed variations over the last decade in the incidence of insulin-dependent diabetes mellitus (IDDM) in the 0- to 19-yr-old age-group and to determine whether incidence has increased in Canterbury, New Zealand. The Canterbury, New Zealand, Diabetes Registry has recorded all incidence cases of diabetes mellitus prospectively since 1982. All IDDM subjects aged 0-19 yr at diagnosis and using insulin are included in the study. Ascertainment is believed to be 100%. Prevalence was recorded at 1 January 1982 and 1 January 1990. Annual incidence for 1982-1990 was determined using age and sex cross-sectional census population denominators. The statistical significance of temporal, age, sex, and seasonal variations in incidence rates was ascertained by Poisson regression models (GLIM statistical software). Prevalence on 1 January 1990 was 115/100,000. Incidence rates during the 9 yr were periodic, with two major peaks--one in the early 1980s, the other in 1989 continuing into 1990. The temporal variation (P less than 0.02) was not age or sex specific. Incidence rates for boys were three- to fourfold higher during peak versus trough years, with a peak level of 20.7/100,000 in 1990. For girls, there was less variation, with a peak rate of 21.6/100,000 in 1990. There has been no significant increase in IDDM incidence over time. The mean rate of incidence across all age-groups for 1982-1990 was 12.7/100,000 person-yr. A significant seasonal association to the onset of IDDM was found only in boys, with incidence rates being significantly higher in winter than in summer (P less than 0.01). IDDM in Canterbury, New Zealand, presents in cycles of incidence peaks and troughs, each spanning 2-3 yr.

Expression of GLUT1 and GLUT4 glucose transporters in skeletal muscle of humans with insulin-dependent diabetes mellitus: regulatory effects of metabolic factors.

Insulin-dependent diabetes mellitus (IDDM) is associated with insulin deficiency and insulin-resistant glucose uptake in skeletal muscle. To investigate the molecular mechanisms for this insulin resistance, we examined the expression of GLUT1 and GLUT4, glucose transporter genes in vastus lateralis muscle from 20 IDDM subjects and 10 nondiabetic controls. Both groups had a mean age of 34 yr and were nonobese. Fasting free plasma insulin levels were similar in control and IDDM subjects but hemoglobin A1c (HbA1c), fasting plasma glucose and free fatty acid levels were significantly higher in IDDM subjects. Euglycemic clamp studies over a range of insulin concentrations in these IDDM subjects previously showed both decreased insulin sensitivity and decreased maximally insulin stimulated glucose utilization. In this study, Northern blotting of muscle ribonucleic acid (RNA) revealed a single 3.0-3.5 kb transcript for both GLUT1 and GLUT4 with no change in messenger RNA (mRNA) size or abundance with IDDM. In IDDM subjects, GLUT1 mRNA levels correlated positively with HbA1c whereas GLUT4 mRNA levels correlated negatively with fasting plasma glucose but not with HbA1c. Neither mRNA correlated with fasting plasma insulin or free fatty acid levels or with daily insulin dose. Immunoblotting of total muscle membranes for GLUT4 showed a single band of mol mass of approximately 45 kilodaltons with no change in size or abundance with IDDM. There was no significant correlation between GLUT4 polypeptide levels and HbA1c, fasting plasma glucose, insulin, or free fatty acids, daily insulin dose, duration of diabetes, or subject age but in IDDM subjects GLUT4 protein levels correlated negatively with body mass index. Thus, impaired expression of glucose transporters in muscle is not essential for the pathogenesis of insulin-resistant glucose uptake in IDDM. No direct regulatory role of chronic glycemic control or plasma insulin levels on GLUT4 expression is evident. In contrast, recent ambient glucose levels may affect levels of GLUT4 mRNA but not GLUT4 protein, suggesting important posttranscriptional regulation of this protein. Since glucose transport has been shown to be rate limiting for glucose utilization in muscle in IDDM, these results suggest impaired translocation or activation of glucose transporters in IDDM.

Islet-reactive T cells are a marker of preclinical insulin-dependent diabetes.

The destruction of pancreatic islet beta cells in insulin-dependent diabetes mellitus (IDDM) is thought to be T cell mediated. To directly identify islet-reactive T cells in asymptomatic, "preclinical" IDDM individuals with islet cell antibodies (ICA), proliferation of peripheral blood mononuclear cells (PBMC) was measured in the presence of sonicated fetal pig proislets. Stimulation indices (mean +/- SD) for [3H]thymidine uptake by PBMC cultured with sonicated proislets were: preclinical IDDM subjects (n = 22) 6.10 +/- 6.50, recent-onset IDDM subjects (n = 29) 3.66 +/- 3.35, Graves' disease subjects (n = 6) 2.17 +/- 0.93, scleroderma subjects (n = 4) 1.65 +/- 0.19 and normal control subjects (n = 14) 1.63 +/- 0.62. 68% (15/22) of preclinical IDDM, 41% (12/29) of recent-onset IDDM and 17% (1/6) of Graves' disease subjects had T cell reactivity greater than the mean + 2 SD of controls. T cell reactivity to proislets was tissue specific, and greater in magnitude and frequency than to human insulin. The majority of preclinical subjects with ICA greater than 20 Juvenile Diabetes Foundation (JDF) units (12/15, 80%) or antibodies to a 64-kD islet autoantigen (11/15, 73%) had significant T cell reactivity to proislets. ICA greater than 40 JDF units, a strong prognostic marker for progression to clinical IDDM, was an absolute index of T cell reactivity. Overall, the frequency of T cell reactivity in preclinical subjects, 68% (15/22), was comparable to that of ICA greater than 20 JDF units or 64-kD antibodies. Greater T cell reactivity to proislets in preclinical subjects accords with the natural history of autoimmune beta cell destruction. The direct assay of islet-reactive T cells in peripheral blood may have prognostic significance for the development of clinical IDDM and should facilitate identification of the primary target autoantigen(s).

Effects of insulin and amino acid infusion on leucine and phenylalanine kinetics in type 1 diabetes.

To evaluate the anabolic effects of hyperinsulinemia and hyperaminoacidemia on amino acid (and protein) metabolism in type 1 (insulin-dependent) diabetes mellitus (IDDM), we studied leucine and phenylalanine kinetics in nine IDDM and seven control subjects, both at basal euglycemic conditions and during a euglycemic hyperinsulinemic clamp (approximately 60-80 microU/ml of plasma free insulin), combined with an intravenous infusion of amino acids (AA), which doubled plasma concentrations of most AA. In the basal state, euglycemia was maintained in IDDM subjects at the expense of a peripheral free insulin level (16 +/- 2 microU/ml) greater (P less than 0.05) than controls (9 +/- 1 microU/ml). Despite that, leucine rate of appearance (Ra), alpha-ketoisocaproate oxidation (approximating leucine-carbon oxidation), and nonoxidative leucine disposal, were greater (P less than 0.05) in IDDM than in control subjects. Phenylalanine Ra was slightly but not significantly greater in IDDM vs. control subjects. During the clamp, at comparable plasma free insulin and amino acid concentrations, oxidation was similar in the two groups, endogenous leucine and phenylalanine Ra remained significantly greater (P less than 0.05) in IDDM than in normal subjects, and leucine disposal tended also to be greater in IDDM subjects. Thus, in IDDM subjects maintained at euglycemia, endogenous Ra of essential amino acid(s) (index of endogenous proteolysis) is increased, both in the postabsorptive state and after hyperinsulinemia combined with hyperaminoacidemia, while leucine utilization for protein synthesis is not impaired.

Insulin-Stimulated Glucose Transport in Circulating Mononuclear Cells From Nondiabetic and IDDM Subjects

The objectives of this study were 1) to evaluate glucose transport and its regulation by insulin in easily accessible human cells, 2) to investigate the glucose transporter isoforms involved, and 3) to establish whether a defect in glucose transport is associated with peripheral insulin resistance, which is common in insulin-dependent diabetes mellitus (IDDM) patients. We measured 2-deoxyglucose (2-DG) uptake in circulating mononuclear cells from 23 nondiabetic adults, 16 adults with IDDM, and 10 children with IDDM. Circulating mononuclear cells were separated from whole blood by Ficoll gradients and incubated with +/- 1 nM insulin. 2-DG uptake was measured after incubation with [3H]2-DG and cell separation through corn oil-phthalate. Cytochalasin B-inhibitable 2-DG uptake (basal and insulin stimulated) was higher in control than in IDDM subjects (P less than 0.001). Insulin significantly increased 2-DG uptake or 3-O-methylglucose uptake in both groups. Basal and insulin-stimulated 2-DG uptake was similar for adults and children with IDDM and did not correlate with age or body mass index in any group or disease duration, insulin dosage, or HbA1c in IDDM. In separated monocytes and lymphocytes, 2-DG uptake increased in response to insulin only in the monocyte population. Insulin dose-response curves indicated maximal stimulation of hexose uptake at 1-2 nM insulin for both control and diabetic subjects and demonstrated a significant decrease in maximal insulin response in the latter. Immunoblotting with specific antibodies revealed that circulating mononuclear cells and separated monocytes express the GLUT1 but not the GLUT4 isoform of the glucose transporter.(ABSTRACT TRUNCATED AT 250 WORDS)

Normalization of Composition of Triglyceride-Rich Lipoprotein Subfractions in Diabetic Subjects During Insulin Infusion With Programmable Implantable Medication System

To investigate whether long-term improved glycemic control by intraperitoneal insulin infusion normalizes the compositional abnormalities of triglyceride (TG)-rich lipoproteins in insulin-dependent diabetes mellitus (IDDM). Seven subjects were studied before and 12-14 mo after initiation of treatment with the programmable implantable medication system (PIMS). Plasma TG levels were measured, and the composition of three TG-rich lipoprotein subfractions (Svedberg flotation [Sf] greater than 400, 100-400, and 20-100) were analyzed before and every 1.5 for 7.5 h after ingestion of corn oil. PIMS significantly improved glycemic control, as measured by mean blood glucose (P less than 0.02), and HbA1 (P less than 0.001, paired t test) levels. Weight loss was also observed during PIMS treatment. Significant changes occurred in the composition of TG-rich lipoprotein subfractions during PIMS treatment in both the fasting (P less than 0.002) and the postprandial (P less than 0.0001) state. Most changes were in the direction of nondiabetic values. PIMS treatment reduced the total cholesterol enrichment in IDDM subjects in all three subfractions in the postprandial state and the very-low-density lipoprotein subfractions (Sf 100-400 and 20-100) in the fasting state. Multivariate analysis showed that the compositional changes were affected by improved glycemic control, as assessed by both mean blood glucose and HbA1, whereas the very-low-density lipoprotein compositional changes were by both the improved glycemic control and body weight. In IDDM subjects during PIMS treatment, there was normalization of most abnormalities in the composition of fasting and postprandial TG-rich lipoproteins, including enrichment in total cholesterol, which is considered atherogenic.

Accuracy of a Filter Paper Method for Measuring Glycosylated Hemoglobin

To compare glycosylated hemoglobin (GH) results obtained by filter paper fingerstick collection and mailed for assay by affinity chromatography with results from a venous sample assayed by ion-exchange chromatography (HbA1) in a local laboratory. Fifty-eight volunteer subjects with insulin-dependent diabetes mellitus (IDDM), aged 5-24 yr, included patients at a referral-based IDDM clinic and subjects in an ongoing research study. We obtained two blood samples from each subject. One was collected by fingerstick onto filter paper, the other by venipuncture into a vacutainer. We sent filter paper samples to the Diabetes Research Laboratory (Univ. of Missouri, Columbia, MO) for analysis. Vacutainer samples were sent to the Clinical Chemistry Department of the Clinical Laboratory, University of Colorado Health Sciences Center. Results were highly correlated (r = 0.89, P = 0.0001). Fifty-nine percent were classified identically when results were normalized to SD units and grouped to suggest levels of clinical concern. The filter paper method is a convenient, accurate measure of glycosylated hemoglobin in young people with IDDM. It should be considered a credible alternative research and clinical tool.

Pituitary Response to Growth Hormone–Releasing Hormone in IDDM: Abnormal Responses to Insulin and Hyperglycemia

In poorly controlled insulin-dependent diabetes mellitus (IDDM), hyperglycemia fails to inhibit the pituitary response to growth hormone-releasing factor (GRF). To evaluate whether this derangement is reversed by a simultaneous elevation of circulating insulin, 0.3 micrograms/kg i.v. GRF 1-40 was administered to nine poorly controlled IDDM subjects (HbA1 greater than 11.1%) with and without concomitant infusion of insulin. In the absence of insulin, the poorly controlled IDDM subjects demonstrated a growth hormone response to GRF similar to that of nondiabetic subjects, despite marked hyperglycemia (approximately 16.8 mM). When insulin was infused into these same patients (insulin clamp) to produce combined hyperinsulinemia (528 +/- 90 pM) and hyperglycemia (16.5 +/- 1.98 mM), the GRF-induced growth hormone rise was markedly exaggerated (65 +/- 11 vs. 20 +/- 4 micrograms/L without insulin infusion, P less than 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 +/- 7 micrograms/L) in five well-controlled diabetic subjects studied under conditions of similar hyperinsulinemia (486 +/- 84 pM) and hyperglycemia (16.41 +/- 0.95 mM). In contrast, in nondiabetic subjects, acute hyperinsulinemia reduced the growth hormone response to GRF. We conclude that the failure of hyperglycemia to block the pituitary response to GRF in poorly controlled diabetes is not attributable to the lack of a coincident increase in circulating insulin. The paradoxical stimulatory effect of insulin on GRF-induced growth hormone release may contribute to the high spontaneous growth hormone levels characteristically seen in poorly controlled insulin-treated patients, and its attenuation after intensive insulin therapy may contribute to the reversal of growth hormone hypersecretion in well-controlled diabetic patients.

Effects of α2-adrenergic blockade on renal hemodynamics in patients with insulin dependent diabetes mellitus

The role of renal α 2-adrenoceptors in the regulation of glomerular filtration and renal perfusion is unknown. We studied the effects of α 2-adrenergic blockade on renal hemodynamics in six patients with insulin-dependent diabetes mellitus (IDDM) and in six healthy subjects. At the basal state, glomerular filtration rate (GFR) was higher in IDDM although the difference from control levels was not statistically significant. Volume expansion, achieved by infusion of isotonic sodium chloride solution, during placebo infusion induced a significant drop in GFR in health subjects but not in IDDM patients. Infusion of the α 2-adrenoceptor antagonist idazoxan did not further modify the effect of volume expansion on GFR. Renal plasma and blood flow as well as filtration fraction were not significantly changed by volume expansion or idazoxan infusion. Plasma renin activity and plasma aldosterone levels decreased during volume expansion in both IDDM and control subjects. In conclusion, volume expansion induced decreased GFR in healthy controls but not in IDDM patients. Since infusion of idazoxan did not affect GFR or other parameters of renal hemodynamics, renal α 2-adrenoceptors do not seem to be involved in the regulation of renal function. Hence, enhanced renal α 2-adrenoceptor activity is not likely to underlie hyperfiltration as seen in IDDM.

Abnormal clearance of postprandial Sf 100-400 plasma lipoproteins in insulin-dependent diabetes mellitus.

Studies were carried out in three normolipidemic non-obese men with insulin-dependent diabetes mellitus (IDDM) and three normal men, to assess whether the clearance of postprandial Sf 100-400 lipoproteins is decreased in IDDM. Sf greater than 100 lipoproteins isolated from plasma 4.5 h after fat ingestion were labeled with 125I and injected into the same subject intravenously. ApoB radioactivity was measured over time in Sf greater than 400, Sf 100-400, and Sf 20-100 lipoproteins isolated from plasma and analyzed using a kinetic model that included both fast and slow delipidation cascades, where lipolysis and uptake of particles by the liver and other tissues were represented. Fractional catabolic rates of Sf 100-400 lipoproteins (min-1) were decreased in diabetic versus control subjects: fast = 0.170 +/- 0.126 versus 0.680 +/- 0.242 (mean +/- SD) (P less than 0.05, two-tailed) and slow = 0.011 +/- 0.006 versus 0.031 +/- 0.015 (P less than 0.05, one-tailed). Kinetic analysis showed that the data were consistent with decreased uptake by the tissues for the fast cascade (diabetic, 0.084 +/- 0.082, vs. control, 0.617 +/- 0.328, P less than 0.05, one-tailed). A similar trend was observed for the slow cascade. There were no significant differences between the two groups in the intraplasma lipolysis rates of Sf 100-400 particles. Analysis of the composition of the injected particles showed that they were total cholesterol (TC)- versus triglyceride (TG)-enriched (P less than 0.001, log-ratio analysis of composition) in IDDM subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of Diabetes in Siblings and Other Relatives of IDDM Subjects

The risk of insulin-dependent diabetes mellitus (IDDM) was examined in siblings of an unselected population (n = 194) of newly diagnosed diabetic individuals less than 30 yr old. From 1 July 1984 to 30 June 1987, diabetic subjects (proband) identified within a geographically defined area of southern Wisconsin were studied. IDDM occurred among siblings of probands in 13.5% of families and was associated with proband age at diagnosis. The highest risk was found for diabetic subjects less than 10 yr old at diagnosis (P = 0.04). We did not find an association between sibling IDDM and proband sex, HLA-DR3/4, duration of symptoms, or ketosis at diagnosis. In addition, the odds ratio (OR) for the association of IDDM in the proband with IDDM in parents and second- and third-degree family members was examined by case-control methodology. Diabetic subjects were matched to two types of control subjects (friends and general population) by age stratum and sex. The OR for IDDM was not increased significantly if parental IDDM or non-insulin-dependent diabetes mellitus (NIDDM) was reported. However, there were very few parents with diabetes among diabetic or control subjects. In 6.4% of diabetic subjects, one parent had IDDM, 54% of whom were fathers. In 4.3% of diabetic subjects, one parent had NIDDM, and 57.1% of these were fathers. The OR for IDDM was significantly increased if second- and/or third-degree relatives had IDDM (OR diabetic subjects vs. general population 2.33 [P less than 0.05)] or NIDDM (OR diabetic subjects vs. friends 2.05 [P less than 0.01]).(ABSTRACT TRUNCATED AT 250 WORDS)