Insulin-dependent Diabetic Individuals Research Articles

Molecular characterization of methicillin-resistant Staphylococcus aureus among insulin-dependent diabetic individuals in Brazil

BackgroundPeople with diabetes mellitus, especially insulin-dependent diabetic patients, are a risk group for staphylococcal infections. Asymptomatic infection with Staphylococcus aureus is common and favors dissemination of the microorganism, rendering these individuals a source of infection. This study aimed to characterize the resistance profile, clonal profile and sequence type, as well as to analyze the prevalence and risk factors for nasal and oropharyngeal carriage of methicillin-susceptible (MSSA) and methicillin-resistant S. aureus (MRSA) isolated from insulin-dependent diabetic individuals in the city of Botucatu, SP, Brazil.MethodsStaphylococcus aureus was collected from the nasopharynx and oropharynx of 312 community-dwelling insulin-dependent diabetic individuals over a period of 3 years (October 2015 to December 2018). The isolates were characterized by susceptibility profiling, detection of the mecA gene, SCCmec typing, and molecular typing by PFGE and MLST. The risk factors associated with S. aureus and MRSA carriage were determined by logistic regression analysis.ResultsThe overall prevalence of colonization with S. aureus and MRSA was 30.4% and 4.8%, respectively. Fifteen of the 112 S. aureus isolates carried the mecA gene; SCCmec type IV was identified in 10 isolates, SCCmec type I in three, and SCCmec type II in two. Among the 15 resistant isolates (MRSA), four were susceptible to oxacillin/cefoxitin by the disc diffusion method and one MSSA isolate was resistant to sulfamethoxazole/trimethoprim. The analysis of risk factors revealed a protective effect of age and lung disease, while lower-extremity ulcers were a risk factor for S. aureus. For MRSA, only male gender was significantly associated as a risk factor in multivariate analysis. Clonal profile analysis demonstrated the formation of clusters among MRSA isolates from different patients, with the identification of ST5-IV, ST5-I, and ST8-IV. Isolates carrying ST398 were identified among MSSA and MRSA (ST398-IV).ConclusionOur findings reinforce the importance of epidemiological studies of S. aureus carriage, especially in populations at high risk of infections such as diabetics. The data suggest widespread dissemination of MRSA in the population of insulin-dependent diabetic patients studied, as well as the emergence of important lineages among these individuals.

Late Conversion to Sirolimus or Everolimus After Pancreas Transplant

BackgroundPancreas transplant is an effective treatment for insulin-dependent diabetic individuals with end-stage renal disease, yet immunosuppression-associated adverse events may adversely affect patient and graft survival. The aim of the study was to document whether mammalian target of rapamycin inhibitors (mTORi) are safe and effective as a second-line drug after pancreas transplant. MethodologyAn observational single-center study was performed in a cohort of 490 simultaneous pancreas–kidney transplant and 45 pancreas-after-kidney transplant individuals after conversion to mTORi (n = 13) owing to adverse events of either tacrolimus or mycophenolate. ResultsmTORi conversion was performed 11.5 ± 10.1 (range, 1-28) months after pancreas transplant, mainly owing to cytomegalovirus infection and gastrointestinal intolerance. We frequently observed clinical complications after mTORi conversion, yet creatinine, eGFR, proteinuria, fasting plasma glucose, HbA1c, and C-peptide remained stable throughout the study (mean follow-up 8.2 ± 5, range 1-17) years, as did the lipid profile (P > .05). However, graft loss occurred in almost 20% of patients owing to chronic alterations. LimitationsThe small number of patients and a single-center cohort were limitations of the study. ConclusionsLate mTORi conversion is a safe and effective approach when tacrolimus or mycophenolate-mediated adverse events occur after pancreas transplant.

Terapia gênica para o diabetes

A administração de insulina exógena tem sido a única forma de tratamento disponível para milhões de indivíduos portadores de diabetes mellitus do tipo 1 (insulino-dependente). Embora o transplante de pâncreas tenha sido empregado com sucesso para um número limitado de pacientes, ele ainda é considerado um procedimento invasivo com alto risco de complicações. Por outro lado, estudos preliminares onde o transplante de ilhotas pancreáticas foi realizado sem o emprego de glucocorticóides no esquema de imunossupressão demonstraram resultados extremamente promissores. Entretanto, o emprego de ilhotas pancreáticas, assim como o transplante de pâncreas, enfrenta o problema da escassez de órgãos disponíveis para transplante. Assim, um dos grandes objetivos da terapia gênica para diabetes é a geração de fontes ilimitadas de células que apresentem secreção normal de insulina em resposta ao estímulo da glicose, capazes de serem transplantadas sem a necessidade de imunossupressão sistêmica. Este artigo tem como finalidade revisar como a terapia gênica pode ser empregada na obtenção desta fonte de células, assim como discutir os últimos avanços no campo da biologia celular e molecular em relação ao crescimento e diferenciação da célula beta.

Aberrant parasympathetic and hemodynamic function distinguishes a subgroup of psychologically distressed individuals with asymptomatic type-I diabetes mellitus

In a previous study, a subgroup of asymptomatic insulin-dependent diabetic individuals (termed IDDM-2) were identified on the basis of diminished parasympathetic cardiac input and elevated heart rate at rest. When compared to another group of asymptomatic IDDM participants (termed IDDM-1), and a nondiabetic healthy control group, the IDDM-2 group displayed elevated blood pressure, supported by elevated total peripheral resistance. Measures of psychological regulation were also taken in this study, and form the basis of this article, which examined whether these IDDM-2 patients differed from the other two groups on these measures. The possible role of glycemic control, IDDM duration, and number of somatic complaints among group differences in psychological regulation was also examined. The IDDM-2 group reported increased psychological distress, as reflected by increased dysphoric or depressive symptoms, trait anxiety, perceived stress, and cynical hostility, as well as decreased optimism and interpersonal, but not family, social support. Glycemic control did not account for any of the group differences in psychological regulation. However, group differences in dysphoria and anxiety were accounted for by differences in somatic complaints, whereas differences in interpersonal social support were accounted for by IDDM duration. Moreover, none of the variables investigated accounted for the diminished optimism of the IDDM-2 group. Therefore, in individuals with IDDM, who would otherwise be considered, after medical examination, as no different from other asymptomatic IDDM individuals, the combination of diminished parasympathetic cardiac input and elevated heart rate was associated with aberrant alterations of both hemodynamic and psychological functioning; the increased psychological distress in these individuals may be influenced, in part, by increased diabetes duration and number of somatic symptoms.

Regulation of glucose transport and expression of GLUT3 transporters in human circulating mononuclear cells: Studies in cells from insulin-dependent diabetic and nondiabetic individuals

We have previously shown that human circulating mononuclear cells (CMCs) respond to physiological concentrations of insulin with a rapid increase in glucose transport rate. The responding cells were found to be the monocytes, and cells derived from individuals with insulin-dependent diabetes mellitus (IDDM) had lower basal and insulin-stimulated glucose transport rates. Of interest, both cell types were found to express the GLUT1 but not the typical insulin-responsive GLUT4 transporter isoform. To further study the mechanisms responsible for stimulation of transport in these cells, we investigated (1) the response to insulin-like growth factor-I (IGF-I) and insulin-mimetic agents, and (2) the expression of other glucose transporter isoforms in CMCs of nondiabetic and IDDM individuals. The time course of insulin-stimulated glucose uptake in CMCs was rapid, reaching a plateau within 30 minutes. CMCs showed a dose-dependent and highly sensitive increase in glucose uptake to IGF-I (maximal response reached at 0.1 to 0.5 nmol/L IGF-I). The IGF-I dose-response curve was similar for CMCs of control and IDDM individuals, but both the basal and maximal response to IGF-I were lower in the diabetic group ( P < .01). CMCs did not respond to vanadate, lithium, hydrogen peroxide, or short incubation (1 hour) with metformin, but glucose uptake increased in response to peroxides of vanadate and longer-duration (14 hours) metformin incubations. The glucose transporter isoforms of separated monocytes and lymphocytes were further investigated by Northern blotting of total RNA with a GLUT3-specific cDNA probe and by Western blotting of total membranes using GLUT3-specific antiserum. Both cell types expressed substantial amounts of GLUT3 mRNA and protein, with significantly more GLUT3 protein in monocytes than in lymphocytes. The results indicate that (1) insulin-mimetic agents active in adipocytes are not uniformly effective in CMCs, (2) CMCs from IDDM individuals show suboptimal maximal response to IGF-I, and (3) insulin-mediated glucose transport in these cells may occur via GLUT1 and/or GLUT3 transporters, but neither isoform is reduced in monocytes or lymphocytes of individuals with IDDM.

Maturation and function of human fetal pancreatic cells after cryopreservation.

If transplantation of endocrine tissue is to become a therapy for a significant number of insulin-dependent diabetic individuals, tissue sources other than adult human islets will be required. Because human fetal pancreatic cells may offer that alternative, we have tried to find the optimal combination of tissue culture and cryopreservation methods for use in transplantation. Islet-like cell clusters (ICCs), cryopreserved according to reported methods for adult human islets, survived poorly after thawing. In contrast, the yield of ICCs was comparable after collagenase digestion of fresh and cryopreserved pancreatic fragments. However, the ICCs derived from cryopreserved tissue contained a higher proportion of nonepithelial cells, and the recovery of insulin was only 28%, as compared with freshly cultured cells. These ICCs had a lower DNA content and a higher rate of DNA synthesis. Moreover, cryopreserved cells released a higher fraction of their insulin content in basal conditions, and their response to theophylline stimulation was slightly lower. ICCs generated from cryopreserved fragments were able to mature morphologically and functionally in vivo after transplantation into athymic nude mice. However, the level and magnitude of the C-peptide response did not equal that of grafted freshly cultured ICCs. Our results indicate that it is possible to generate ICCs from cryopreserved human fetal pancreas with the capacity, after transplantation, to release insulin appropriately in response to glucose. However, possibly because undifferentiated pancreatic cells may be particularly vulnerable to cryopreservation, current methods may need to be improved for optimal tissue retrieval.

Alterations of purine metabolism in mononuclear cell populations of first degree relatives of insulin-dependent diabetic individuals with disturbed glucose tolerance.

In a T lymphocyte and macrophage-depleted mononuclear cell population of the peripheral venous blood of 10 of 41 first degree relatives of insulin-dependent diabetic individuals who had or had had disturbed glucose tolerance adenine uptake rates were significantly increased, the relative adenine incorporation rates into the adenine nucleotides, however, were diminished. Values were compared with those of 30 controls. In 7 of 9 investigated individuals with increased adenine uptake rates antibody-dependent cellular cytotoxicity against rat Langerhans islets (ADCC) was increased in the same cell population. In these individuals the number of diabetes manifestations was relatively high. Adenine uptake rates, ADCC and glucose tolerance changed with time.

Concentrations and adenine metabolic rates of adenine nucleotides in mononuclear cell populations of type I (insulin-dependent) diabetic individuals in different states of metabolic compensation. Preliminary results.

Concentrations and adenine metabolic rates of adenine nucleotides in mononuclear cell populations of type I (insulin-dependent) diabetic individuals in different states of metabolic compensation. Preliminary results.

Metabolic effects of high-carbohydrate, high-fiber diets for insulin-dependent diabetic individuals

The metabolic effects of high-carbohydrate (70%), high-fiber (70 g) (HCHF) and low-carbohydrate (39%), low-fiber (10 g) (LCLF) diets were examined for 10 subjects with insulin-dependent diabetes mellitus (IDDM). After a 1-wk control period subjects on a metabolic ward were randomly allocated to HCHF or LCLF diets for 4 wk. After a 6-wk washout period subjects re-entered the metabolic ward for 4 wk on the alternate diet. Artificial-pancreas studies were performed on each diet for measurement of insulin requirements. Compared with the LCLF diet, the HCHF diet reduced basal insulin requirements (P less than 0.025), increased carbohydrate disposed of per unit insulin (P less than 0.0008), and lowered total (P less than 0.0004) and high-density-lipoprotein cholesterol (P less than 0.0013). Glycemic control and other lipid fractions did not differ significantly. These results suggest that in IDDM patients, HCHF diets enhance peripheral glucose disposal, decrease basal insulin requirements, and lower total cholesterol without altering glycemic control or triglycerides.

Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes.

Cytoplasmic islet cell antibody-negative (ICA-; less than 20 Juvenile Diabetes Foundation units, n = 1670) and ICA+ (n = 42) first-degree relatives of type I (insulin-dependent) diabetic individuals were studied for competitive insulin autoantibodies (CIAAs) with a radioassay. Overall, 3.7% of first-degree relatives (64 of 1712) were CIAA+. Of ICA- relatives, 2.7% (45 of 1670) exceeded the upper limit of our normal CIAA range (greater than 39 nU/ml), and 45% (19 of 42) of ICA+ relatives exceeded this normal range. Follow-up serums for repeat CIAA determination have been obtained from 16 of the nondiabetic CIAA+/ICA- individuals (time between samples, 0.4-5.8 yr). Fourteen of these 16 (87%) CIAA+/ICA- relatives were found to still be positive on follow-up, and 2 of the relatives who were positive on the first determination were negative on their follow-up test. With a mean follow-up of approximately 2 yr, 4 of 45 (9%) of the CIAA+/ICA- relatives, 5 of 23 (22%) of the ICA+/CIAA- relatives, and 12 of 19 (63%) of the CIAA+/ICA+ relatives developed diabetes. Life-table analysis indicated that, overall, 53% of CIAA+ relatives become diabetic after 5 yr of follow-up versus 65% of ICA+ relatives. Also by life-table analysis, the predicted risk after 5 yr of follow-up for progression to diabetes is 17% for CIAA+/ICA- relatives, 42% for ICA+/CIAA- relatives, and 77% for CIAA+/ICA+ relatives. The highest rate of progression to diabetes was found in ICA+ relatives with CIAA levels greater than 150 nU/ml (100% projected to be diabetic within 5 yr, P less than .008 vs. ICA+/CIAA- relatives).

Sequence analysis of HLA class II genes from insulin-dependent diabetic individuals

To examine the nature of HLA-linked genetic susceptibility to insulin-dependent diabetes mellitus (IDDM), we compared HLA class II gene sequences from IDDM patients and control individuals. Genomic libraries were constructed from two siblings with IDDM, typed serologically as DR3,w6 and DR3,4. These libraries represent the HLA haplotypes (DR3, DR4) most frequently associated with IDDM, as well as one haplotype found less often. Individual genomic clones were identified and assigned to specific loci and haplotypes. The nucleotide sequence was then determined from the variable second exon from the HLA-DQα, DQß, and DRß genes from all three haplotypes. Sequence variation within the DQα genes could not be correlated with the disease. For all three haplotypes, the DQα sequence from the IDDM patient was identical to the DR-matched control sequence. Similarly, for the DR3 haplotype, the DQß sequences matched all control DR3 alleles. The DQß sequence from the DR4 haplotype was identical to the predominant DR4 allele (DQß 3.2) but differed at four amino acid residues from the other major DR4 DQß sequence (DQß3.1) found rarely among IDDM patients. Sequence analysis of the DQß gene from the DRw6 haplotype revealed a new allele that differed from the DQß allele from a control DR6 allele at two residues. The DRß genes from these three haplotypes also did not show any sequence features uniquely associated with IDDM, although the frequency of certain allelic variants in all three of these haplotypes may be altered in the IDDM population. A particular group of amino acids was found to be shared between the DRß-1 alleles from the DR4 and DRw6 haplotypes and may be involved in genetic susceptibility to IDDM.

Computer-assisted insulin dosage adjustment.

We report our first experience with a new microprocessor device for assisting individuals with diabetes in the adjustment of insulin therapy. The computer weighs 200 g and can receive, store, and analyze patient-entered capillary blood glucose (CBG) data on an ongoing basis. Changes in the injected mixtures of short- and intermediate-acting insulins are recommended according to algorithms designed to bring the premeal CBG levels to any desired target value set by the physician. Throughout the present study, the premeal target glucose level was set to 110 mg/dl. Seven (type I) insulin-dependent diabetic individuals ranging in age from 11 to 43 yr were selected to participate in the first use of a BCMC (Better Control Medical Computers, Inc., Toronto, Ontario, Canada) computer on an outpatient basis. All subjects were concerned about diabetes control and were fully informed about as well as thoroughly practiced in the use of manual insulin dosage adjustment schemes, based on approximately equal to 4 times daily CBG estimation, as currently taught in our diabetes clinics. During the last 7 days of the control period of self-adjustment, their mean +/- SEM CBG levels (measured before breakfast, lunch, dinner, and bedtime snack) were, respectively, 178 +/- 20, 187 +/- 35, 208 +/- 22, and 207 +/- 13 mg/dl. Immediately after the control period they were given the device and were instructed in the procedure for entering glycemic data and following manufacturer's recommendations in regard to insulin dosages. This experimental period lasted 8 wk and the outcome was assessed as before. Thus, 8 wk after starting daily use of the instrument, all glycemic values measured as before had fallen significantly (P less than 0.005-0.05) closer to normal: 116 +/- 9, 110 +/- 6, 148 +/- 15, and 135 +/- 9 mg/dl, respectively. Concurrently there was also a significant (P less than 0.01) reduction in the variability of glycemia measured before the main meals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Insulin Pump Treatment for One Year on Renal Function and Retinal Morphology in Patients with IDDM

The effect of strict metabolic control for 1 yr on renal function and retinal morphology was estimated in 24 insulin-dependent diabetic individuals (age 29 +/- 8 yr, diabetes duration 10 +/- 6 yr) with Albustix negative urine and minimal or no background retinopathy before the study. They were randomized to conventional insulin treatment (CIT) or continuous subcutaneous insulin infusion (CSII) with a portable pump. During CSII treatment the metabolic status was significantly improved and glomerular filtration rates (GFR) were found to decline (from 130 +/- 18 to 116 +/- 15 ml/min/1.73 m2, P less than 0.01). The mean value of urinary albumin excretion (UAE) was not statistically significantly reduced (from 15.3 +/- 24.1 to 6.8 +/- 1.5 mg/24 h, P greater than 0.1). In the CIT group both GFR and UAE values were unchanged. In all subjects before treatment we found a positive correlation between the metabolic status, estimated by the HbA1c values, and GFR as well as UAE values, respectively (r = 0.64, P less than 0.01 and r = 0.42, P less than 0.05). We conclude that elevated GFR values can be reduced toward normal level by insulin pump treatment for 1 yr. Retinal morphology was found to deteriorate in four of 12 CIT subjects and in three of 12 CSII subjects. However, the progression was mild and in most individuals only due to a slight increase in the number of microaneurysms. Pump treatment did not induce proliferation and "cotton-wool" exudates were not detectable in any pump subject after 1 yr of treatment. We conclude that CSII treatment for 1 yr was unable to stop the progression of retinopathy in individuals with minimal or no retinopathy on entering the study. On the other hand, pump treatment did not induce cotton-wool exudates or proliferation in these subjects as previously reported in subjects with more severe retinopathy before CSII treatment.

Insulin-mediated glucose uptake in nondialyzed and dialyzed uremic insulin-dependent diabetic subjects.

A three-step euglycemic insulin clamp was performed in six matched groups: nine healthy subjects, 10 insulin-dependent diabetic (IDD) subjects with normal kidney function, 10 nondiabetic uremic subjects, six nondialyzed uremic IDD subjects, seven uremic IDD subjects on chronic hemodialysis (HD), and six uremic IDD subjects on chronic ambulatory peritoneal dialysis (CAPD). Insulin was infused sequentially at rates of 0.5 (step 1), 2.0 (step 2), and 4.0 (step 3) mU X kg-1 X min-1. Each dose was given for 120 min; however, in the IDD subjects with fasting hyperglycemia, step 1 of the clamp was slightly extended. Average serum free insulin levels at steady state ranged from 22 to 342 microU/ml and were comparable in all groups. Step 3 glucose infusion rate (GIR), the last 30 min of the infusion period, was extremely suppressed in nondialyzed uremic IDD subjects, amounting to 53% of that in healthy subjects (7.7 +/- 0.7 versus 14.4 +/- 0.9 mg X kg-1 X min-1, P less than 0.001) indicating severe insulin resistance in peripheral tissues. As expected, step 3 glucose disposal was also reduced in IDD subjects with normal kidney function (12.4 +/- 0.6 mg X kg-1 X min-1) and nondiabetic uremic subjects (9.2 +/- 0.6 mg X kg-1 X min-1) as compared with healthy subjects (P = 0.06 and P less than 0.001, respectively). The pronounced impairment of insulin responsiveness in nondialyzed uremic IDD subjects was almost equal to the sum of the defects in nondiabetic uremic and IDD subjects with normal kidney function.(ABSTRACT TRUNCATED AT 250 WORDS)

Products of therapeutic insulins in the blood of insulin-dependent (type I) diabetic patients.

The tendency of insulin in high concentrations to self-associate and the widespread presence of insulin-degrading enzymes suggest that fragments and/or aggregates of insulin may circulate in normal and insulin-dependent diabetic (IDDM) individuals. To examine this possibility, we have analyzed, by sensitive physicochemical methods, immunoreactive insulin (IRI) taken from the blood of 9 healthy volunteers and 12 insulin-dependent diabetic patients. IRI from the blood of the normal volunteers was composed of 6000 (91.0 +/- 1.4%) and 9000 (9.0 +/- 1.4%) molecular weight (mol wt) material. By 10% polyacrylamide disc gel electrophoresis (PAGE) and reverse-phase, high-performance liquid chromatography (HPLC), the 6000 mol wt material was indistinguishable from human insulin standards and insulin fragments were not found. C-peptide reactivity in the 9000 mol wt material confirmed the expected presence of proinsulin and intermediates of proinsulin conversion. IRI harvested from the blood of 12 C-peptide-negative IDDMs, using a variety of insulin preparations, also separated into 6000 (80.5 +/- 3.9%) and 9000-12,000 (19.5 +/- 3.9%) mol wt material. By HPLC, 6000 mol wt IRI was either pork insulin (in volunteers using pure pork insulin) or a mixture of beef (approximately 90%), pork (approximately 10%) and deamidated beef (trace) insulin in those using a beef-pork mixture. However, the 9000-12,000 mol wt material had characteristics entirely distinct from proinsulin of either human or animal origin: C-peptide reactivity was undetectable using any of three sensitive radioimmunoassay systems, on PAGE it migrated more rapidly than proinsulin-like material, and in contrast to proinsulin, it was unaffected by proteolytic degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

The Etiology of Incapacitating, Brittle Diabetes

Incapacitated brittle diabetic subjects are a small subset of insulin-dependent diabetic individuals who are unable to maintain a normal lifestyle because of frequent disruptions secondary to severe hyperglycemic and/or hypoglycemic episodes. Thirty incapacitated patients were referred for evaluation because the cause of their diabetic instability could not be determined by their personal physicians despite extensive patient training in correct diabetes management, frequent hospitalizations for observation, and multiple diagnostic testing. From the 30 patients, a diagnostic algorithm was developed (described in the companion article) from which the etiology of brittle diabetes could be established in 29. This article provides the clinical characteristics of each of the 30 patients, a description of the etiologic categories of brittle diabetes, and the clinical follow-up from the time that the etiologic diagnosis was established and treatment recommended. Although extensive medical records were sent with each patient, without prospective objective testing under rigidly controlled conditions, the correct etiologic diagnosis would not have been evident from the clinical presentation of the patient. Of equal importance in identifying the etiology of brittle diabetes was the acceptance and cooperation of the referring physician in providing close follow-up and repeat insulin challenge testing when necessary. In this referred patient population, eight subjects had factitious disease, eight were malingering, seven had communication deficits, two had gastroparesis, two had systemic insulin resistance, two had miscellaneous causes of brittle diabetes, and one patient remained undiagnosed.(ABSTRACT TRUNCATED AT 250 WORDS)

Diarrhea and metformin in a diabetic clinic.

In a questionnaire-based survey of 285 randomly selected diabetic patients, diarrhea was found to occur in 8%; this was found to be similar to that in 150 nondiabetic control patients attending other medical clinics (8%). When the diabetic patients were divided into separate therapeutic groups, metformin-treated (with or without sulfonylureas) patients had a markedly greater prevalence of diarrhea (20%) than those not on this drug (6%). A majority of patients with metformin-associated diarrhea had soiling of clothes as a problem, while at least two complained of frank loss of control over their anal sphincter. These patients did not have autonomic neuropathy, and in all who stopped this drug, diarrhea settled within 2-5 days. Only 6% of insulin-dependent diabetic individuals (IDD) had diarrhea, one of whom had explosive nocturnal stools with incontinence and features diagnostic of autonomic neuropathy. Metformin is by far the commonest cause of diarrhea and incontinence in our diabetic clinic, where it is used routinely. In contrast, diarrhea due to autonomic neuropathy is rare.

HLA-D region β-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals

The human HLA-D histocompatibility region encodes class II antigens each of which consists of two polypeptide chains (alpha and beta) inserted in the plasma membrane. These molecules are implicated in the regulation of the immune response but several human diseases are also found to be associated with certain HLA-DR antigens. The occurrence of insulin-dependent (type I) diabetes (IDDM) is strongly associated with HLA-DR3 and/or 4 (ref. 5). The class II antigens, however, show a marked genetic polymorphism associated with the beta-chains which seem, from hybridization studies, to be encoded by several genes. We have therefore used the beta-chain cDNA probe, pDR-beta-1 (refs 8, 10) to test whether there are differences in hybridization pattern between DNA from healthy individuals and diabetic patients, after digestion with restriction endonucleases. Among the HLA-DR 4 and 3/4 individuals, the IDDM patients showed an increased frequency of a PstI 18 kilobase (kb) fragment. A BamHI 3.7 kb fragment, frequent among controls (30-40%), was rarely detected in the IDDM patients (0-2%). These differences may be related to susceptibility to develop the disease.

The effect of postprandial exercise on meal-related glucose intolerance in insulin-dependent diabetic individuals.

Although exercise is a central therapeutic modality in insulin-dependent diabetic patients, its prescription and expected effects have remained far less precise than the concurrent modalities of insulin and diet. To quantify the potential benefit of exercise on meal glycemic excursions, eight insulin-dependent diabetic subjects were studied on two separate days during breakfast and lunch, with and without 45 min of moderate exercise, starting 30 min after breakfast. All other variables were kept constant, including their usual insulin doses, which were given subcutaneously in the abdomen. Fasting glycemias were brought to comparable levels by overnight insulin infusion (rest day: 110 ± 9 mg/dl; exercise day: 105 ± 9 mg/dl). Postprandial exercise reduced peak glycemia for breakfast (270 ± 22 versus 203 ± 22 mg/dl) and lunch (270 ± 16 versus 170 ± 20 mg/dl, P &amp;lt; 0.05) for the group as a whole on rest day and exercise day, respectively. Three types of individual responses were seen. Five subjects showed an improved glycemic excursion with exercise during both breakfast and lunch. In two subjects only the lunch response was significantly improved. One subject showed no effect of exercise. The failure to demonstrate a lowering of glycemia with breakfast appears to be related to the persistent use of fatderived fuels in these subjects. This is suggested by a lower respiratory quotient (RQ), and elevated free fatty acid and 3-hydroxybutyrate concentrations. Plasma “free” insulin and glucagon concentrations could not account for these observations. Thus, the majority of subjects showed improved glucoregulation related to exercise performed postprandially. If adequately insulinized, conventionally treated diabetic individuals can benefit from strategically timed exercise.

Immunopathology of Juvenile-onset Diabetes Mellitus: I. IgA Deficiency and Juvenile Diabetes

There is an increased prevalence (P less than 0.001) of IgA deficiency in children with juvenile-onset insulin-dependent diabetes mellitus (9/366) but not in adults with insulin-dependent diabetes (0/421). The juvenile diabetics with IgA deficiency have other immune-associated diseases, such as thyroiditis and chronic active hepatitis, and have a history of infections. Four of the nine IgA-deficient diabetics we studied have autoantibodies to endocrine organs. Seven of eight have the HLA-B8, a proportion significantly (P less than 0.05) greater than control populations. Based on the clinical findings of IgA deficiency and multiple autoantibodies in patients with ataxia-telangiectasia and chronic mucocutaneous candidiasis, diseases associated with thymus deficiency, we suspect that thymus deficiency and autoimmunity may play a role in the pathogenesis of some types of juvenile-onset diabetes mellitus. In addition, an excess morbidity of the IgA-deficient juvenile diabetic population may explain the lack of IgA deficiency in older insulin-dependent diabetic individuals.