We intensively studied 5 islet cell-antibody-positive (ICA+) first-degree relatives of type I (insulin-dependent) diabetic patients before overt diabetes. In total, 55 intravenous glucose tolerance tests (IVGTTs) and 83 fasting plasma glucose determinations were made over a maximum 4-yr period before diabetes. The 5 prediabetic relatives (not diabetic when initially studied but subsequently progressed to overt diabetes) as a group showed a progressive rise in fasting glucose (r = 0.58, P less than 0.001, slope = 23.1 mg.dl-1.yr-1) and glucose at 60 min in IVGTT (r = 0.46, P = 0.01, slope = 47.5 mg.dl-1.yr-1) beginning 1.5 yr before diabetes. During the 4.0- to 1.5-yr period before overt diabetes, no change was observed in fasting glucose or glucose at 60 min on IVGTT (fasting glucose: r = 0.21, P = 0.18, slope = 2.1 mg.dl-1.yr-1; 60-min glucose: r = 0.08, P = 0.72, slope = 2.9 mg.dl-1.yr-1). The positive predictive value for a fasting glucose greater than 108 mg/dl to be within 1.5 yr of diabetes was 100% (11 of 11 values). The negative predictive value of a stimulated insulin (1-min + 3-min insulin - 2 X basal insulin) level greater than 24 microU/ml to be greater than 1.5 yr from diabetes was 90% (9 of 10 values) and 100% (10 of 10 values) at greater than 1 yr from overt diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytoplasmic islet cell antibody–negative (ICA−; <20 Juvenile Diabetes Foundation units, n = 1670) and ICA+ (n = 42) first-degree relatives of type I (insulindependent) diabetic individuals were studied for competitive insulin autoantibodies (ClAAs) 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 (>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 ∼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 >150 nU/ml (100% projected to be diabetic within 5 yr, P < .008 vs. ICA/CIAA relatives).

In an initial cross-sectional study, 29 female and 25 male nondiabetic weaned nonobese diabetic (NOD) mice of various ages (age range 30–300 days, mean 108 ± 10 days) and 11 unweaned NOD pups were evaluated for competitive insulin autoantibodies (CIAAs) with a fluid-phase radioassay. Eleven of 54 (20%) weaned NOD mice had CIAA levels above the range (>39 nU/ml) of 81 control mice. The group of NOD mice that progressed to diabetes had a significantly higher level of CIAAs than NOD mice that did not progress to diabetes (NOD mice progressing to diabetes: CIAA 63 ± 12 nU/ml; NOD mice not progressing to diabetes: CIAA 8 ± 4 nU/ml; P < .02). Seven of 11 (64%) NOD mice having CIAA concentrations exceeding the normal range progressed to diabetes, whereas only 4 of 43 (9%) NOD mice progressed to diabetes without detection of elevated CIAAs (Fisher's exact test, P < .0005). The relative risk of progressing to overt diabetes with CIAA levels >39 nU/ml was therefore 17 (P < .005), giving a positive predictive value of 64%, a negative predictive value of 91%, and an overall accuracy of 85%. None of 11 unweaned NOD pups had CIAA levels above the normal range (mean −9.4 ± 4.9 nU/ml). At 6 wk of age, 37% of female NOD mice were CIAA+, whereas none of the male animals exceeded the normal range at this age (38 ± 13 vs. 5 ± 6 nU/ml, P < .05). Results of testing two samples during the follow-up of NOD mice indicated that individual NOD mice positive or negative for CIAAs generally remain positive or negative, and CIAA concentrations often increased in initially positive animals. Fourteen NOD mice were included in a prospective study, and CIAAs were evaluated at 9-wk intervals over a follow-up of 8 mo. Four of these NOD mice had elevated CIAA levels, and 3 of 4 CIAA+ mice developed overt diabetes, whereas none of the NOD mice with CIAAs <39 nU/ml developed diabetes. These results were consistent with the results of our cross-sectional study. From these data, we concluded that 1) NOD mice express CIAAs to insulin before progressing to overt diabetes, 2) these antibodies appear after weaning, and 3) CIAA analysis can identify animals with increased or decreased risk of progressing to overt diabetes.

High surface area platinum subjected to the appropriate electrical potential cycling regimes exhibits considerable electrocatalytic activity towards glucose oxidation. We have developed a special data processing method, the compensated net charge (CNC) method, to take advantage of the electrocatalytic activity of platinum. This method involves the determination of the net oxidation charge during one complete cycle of a cyclic voltammogram applied to the platinum electrode in a potentiodynamic mode. Under these conditions, the electrode response is very sensitive to glucose, completely insensitive to urea, and only moderately sensitive to amino acid concentration changes. Earlier work with other endogenous and exogenous potential co-reactants shows little interference. Data obtained in vitro and in vivo will be presented and discussed.

Diabetes/Metabolism ReviewsVolume 3, Issue 4 p. 873-891 Article The “natural” history of type I diabetes G. S. Eisenbarth, G. S. Eisenbarth Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, New England Deaconess Hospital, Boston, MassachusettsSearch for more papers by this authorJ. Connelly, J. Connelly Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, New England Deaconess Hospital, Boston, MassachusettsSearch for more papers by this authorJ. S. Soeldner, J. S. Soeldner Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, New England Deaconess Hospital, Boston, MassachusettsSearch for more papers by this author G. S. Eisenbarth, G. S. Eisenbarth Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, New England Deaconess Hospital, Boston, MassachusettsSearch for more papers by this authorJ. Connelly, J. Connelly Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, New England Deaconess Hospital, Boston, MassachusettsSearch for more papers by this authorJ. S. Soeldner, J. S. Soeldner Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, New England Deaconess Hospital, Boston, MassachusettsSearch for more papers by this author First published: October 1987 https://doi.org/10.1002/dmr.5610030404Citations: 31AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume3, Issue4October 1987Pages 873-891 RelatedInformation

Limited joint mobility (LJM) of the hand was studied by visual examination in 361 diabetic outpatients aged 11 to 83 years, and 45 non-diabetic controls, without evidence of arthritis. LJM was evident in 58% of diabetic subjects and 4% of controls (p less than 0.001). LJM was noted in 131 (55%) of the 238 patients with insulin-dependent diabetes mellitus (IDDM) as opposed to 31 of the 41 patients (76%) with non-insulin-dependent diabetes mellitus (NIDDM). LJM occurred in 60 of the 82 diabetic subjects (73%) receiving insulin therapy who developed diabetes after the age of 35 years. LJM was significantly related to duration of diabetes in the patients with IDDM less than 40 years of age but was not associated with duration in the patients with NIDDM. A significant association of LJM and neuropathy was noted in patients less than 40 years of age with less than 20 years of diabetes. A significant association of LJM and retinopathy was also noted in those less than 40 years of age with less than 30 years of diabetes. There was no association of LJM and nephropathy regardless of age or duration of diabetes.

In a prospective study to evaluate the prevalence and predictive potential of circulating islet-cell antibodies, we have screened 1723 "normal" first-degree relatives (parents, siblings, and offspring) of patients with insulin-dependent diabetes mellitus. The prevalence of islet-cell antibodies on initial screening was 0.9 per cent (16 of 1723). Over a maximal follow-up period of two years, insulin-dependent diabetes mellitus developed in 2 of 16 relatives with islet-cell antibodies and in 1 of 1707 without antibodies. In addition, 6 of 12 nondiabetic relatives with islet-cell antibodies had abnormally low insulin responses--below the third percentile in 6 and below the first percentile in 4--on their initial intravenous glucose challenge. Thus, prospective islet-cell antibody screening of high-risk first-degree relatives, in combination with intravenous glucose-tolerance testing, is capable of identifying immunologically abnormal persons with profoundly diminished beta-cell function, who are presumably at increased risk of insulin-dependent diabetes mellitus.

Plasma lipids and oral glucose tolerance were determined in 67 normal control subjects (age range 19–67 yr) and 150 individuals (17–69 yr) who were offspring of two type II diabetic parents. Age- and weight-adjusted analyses of covariance were performed for lipids and for glucose and insulin responses. For both men and women, the mean concentrations of total, low-density-, and high-density-lipoprotein-cholesterol and of triglycerides in the offspring with normal glucose tolerance (N = 109) were similar to respective controls. For offspring with abnormal glucose tolerance (N = 41), the mean levels of total cholesterol, LDL-cholesterol, and triglycerides were significantly elevated (P = 0.02 or less) in women but not in men. The mean HDL-cholesterol levels were 20% lower and LDL/HDL-cholesterol ratios 60% greater in women with abnormal glucose tolerance, whereas no significant differences existed for any of the lipid fractions in men, compared with respective controls. Both men and women with abnormal glucose tolerance had a comparable magnitude of hyperglycemia as well as hyperinsulinemia. These observations indicate that significant alterations in plasma lipids exist in individuals with mild, asymptomatic glucose intolerance and there are important sex differences in lipid metabolism in the early stage of diabetes, despite comparable degrees of glucose intolerance and insulin responses.

Annals of the New York Academy of SciencesVolume 428, Issue 1 p. 263-278 An Implantable Electrochemical Glucose Sensora HARRY LERNER, HARRY LERNER Giner, Inc. Waltham, Massachusetts 02154Search for more papers by this authorJOSE GINER, JOSE GINER Giner, Inc. Waltham, Massachusetts 02154Search for more papers by this authorJ. STUART SOELDNER, J. STUART SOELDNER E. P. Joslin Research Laboratory Boston, MassachusettsSearch for more papers by this authorCLARK K. COLTON, CLARK K. COLTON Massachusetts Institute of Technology Cambridge, MassachusettsSearch for more papers by this author HARRY LERNER, HARRY LERNER Giner, Inc. Waltham, Massachusetts 02154Search for more papers by this authorJOSE GINER, JOSE GINER Giner, Inc. Waltham, Massachusetts 02154Search for more papers by this authorJ. STUART SOELDNER, J. STUART SOELDNER E. P. Joslin Research Laboratory Boston, MassachusettsSearch for more papers by this authorCLARK K. COLTON, CLARK K. COLTON Massachusetts Institute of Technology Cambridge, MassachusettsSearch for more papers by this author First published: June 1984 https://doi.org/10.1111/j.1749-6632.1984.tb12302.xCitations: 23 a Supported in part by National Institutes of Health Grant AM-18352, the Doll Medical Research Foundation, Inc. (New Hyde Park, NY), and the Joslin Diabetes Center, Inc. (Boston, MA). AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume428, Issue1Technology Impact: Potential Directions for Laboratory MedicineJune 1984Pages 263-278 RelatedInformation

The reliability and reproducibility of peripheral blood flow data obtained by a noninvasive electromagnetic flowmeter were tested using seven male and three female volunteers aged 15-46 years. Each subject was studied under multiple testing conditions in which time, subject's metabolic state, and electrode placement were varied. Each condition was repeated within 1 to 8 weeks to obtain test-retest data. Intraclass reliability coefficients of 0.864-0.998 were obtained on all pulsatile components both within a given measurement sessions and from one day to the next. The size and shape of the waveforms obtained from the data did not significantly differ from one another, thus indicating excellent reproducibility. No significant differences were found between data obtained from the right leg and that obtained from the left. The noninvasive electromagnetic flowmeter was found capable of providing reliable and reproducible data. For data analysis, the second of two consecutive curves seems to be the best choice for clinical assessment.

Quadriceps (Q) and gastrocnemius (G) muscle capillary basement membrane width (CBMW) were measured in 18 pairs of monozygotic (MZ) twins. Thirteen of these twin pairs were discordant for insulin-dependent diabetes (IDD) and five pairs were concordant for either IDD (two pairs) or for non-insulin-dependent diabetes (NIDD). In 12 of the 13 nondiabetic (ND) twin mates of IDD, 50 oral glucose tolerance tests performed in the years before or after determination of CBMW revealed mean blood glucose levels in the 36-52 percentile range, compared with normal controls. The mean (+/-SD) age at the onset of IDD in discordant twins was 18.7 +/- 10.1 (range 8-37) yr and the mean duration of discordance at the time of biopsy was 13.6 +/- 8.3 (range 3-32) yr. CBMW data were compared within each twin (Q versus G) and between twin mates and age- and sex-matched controls. Overall, CBMW of IDD twins was greater than that of their ND twin mates. Differences between IDD and ND twins, however, were much more marked in gastrocnemius (1859 +/- 643 versus 1222 +/- 307 A, P less than 0.0003) than in quadriceps (1291 +/- 319 versus 1112 +/- 302 A; P less than 0.04). CBMW in gastrocnemius was significantly thicker than that in the quadriceps of IDD twins (t = 4.55, P less than 0.0008) but not in their ND twin mates (t = 1.15, P less than 0.27). CMBW was significantly thicker in IDD than in their ND twin mates (in quadriceps and/or gastrocnemius) in 10 of the 12 twin pairs.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulsatile arterial blood flow was studied in 20 normal (N), 20 short-term (STIDDM; mean: 5.17 yr), and 20 long-term insulin-dependent diabetic patients (LTIDDM; mean: 14.76 yr) between the ages of 18 and 30 yr with no clinically detectable peripheral vascular disease. Measurements were taken from waveforms obtained noninvasively using an electromagnetic flowmeter at rest and immediately after a 3-min isometric exercise challenge of the right leg. At rest, both groups of diabetics exhibited minute flow values similar to those in the normal group. This was achieved, however, by increased vasodilation in peripheral tissues as indicated by a difference in waveform configuration. Diabetic subjects showed a significantly smaller peak flow, a less steep ascending and descending slope, and a higher minute heart rate than normal controls. After 3 min of isometric exercise, the diabetic groups exhibited significantly less minute flow, flow/pulse, and a more vasodilated flow pattern similar to that recorded at rest. In addition, the LTIDDM group showed significantly less arterial elasticity than N or STIDDM groups as indicated by a shorter propagation time. These findings imply that apparent functional changes in pulsatile arterial blood flow occur early in the time course of diabetes and are independent of duration.

Cunningham, L. N.; Labrle, C.; Soeldner, J. S.; Gleason, R. E.; Anderson, N.; Joslin, E. P. Author Information

Methods are presented for assessing insulin therapies using a physiologic pharmacokinetic model of glucose homeostasis in man. The model is composed of simultaneous differential equations that represent physiologic compartments and spaces in which glucose and insulin are distributed and undergo metabolic reactions. The model is used to simulate clinical experiments in which blood glucose concentration is controlled by artificial device therapies. Predictions of the theoretical model for responses of normal and diabetic individuals to standard intravenous and oral glucose tolerance tests are compared to clinical data. Reasonable agreement is obtained between predictions of the computer simulations and clinical data for normal individuals. The responses of a diabetic person to oral glucose tolerance tests are simulated by removal of the pancreas from the glucose homeostasis model and introduction of insulin into the model by a prescribed therapy. Model simulations reaffirm expectations concerning the poor blood glucose control attainable by intramuscular insulin injection. Simulations of blood glucose regulation by an artificial pancreas using closed-loop feedback control for controlling insulin delivery rate reveal hyperinsulinemia that results in a net shift in the deposition of a glucose load from liver to peripheral tissues. Simulations of this system in which the time delay for glucose measurement is varied from 1.5 to 30 min show that increases in sensor delay result in progressive loss in glucose regulation, exacerbation of hyperinsulinemia, and increased insulin requirements.