Shirish C. Shah

A Randomized Trial of Intensive Insulin Therapy in Newly Diagnosed Insulin-Dependent Diabetes Mellitus

A period of early, intensive insulin treatment is thought to improve subsequent beta-cell function in insulin-dependent diabetes mellitus (IDDM). To study this hypothesis, we randomly assigned adolescents with newly diagnosed IDDM to receive either conventional treatment (n = 14) (NPH insulin, 1 U per kilogram of body weight per day, in two divided doses) or an experimental treatment (n = 12) (a two-week hospitalization with maintenance of blood glucose levels between 3.3 and 4.4 mmol per liter by continuous insulin infusion delivered by an external artificial pancreas [Biostator]). During the two-week intervention, the experimental-therapy group received four times more insulin than the conventionally treated group, and their endogenous insulin secretion was more completely suppressed, as evidenced by a urinary C-peptide excretion rate one seventh that of the conventionally treated group. After the first two weeks, both groups were treated similarly and received similar amounts of insulin. At one year, the mean (+/- SEM) plasma level of C peptide was significantly higher after mixed-meal stimulation in the experimental-therapy group than in the conventionally treated group (0.51 +/- 0.07 vs. 0.27 +/- 0.06; P less than 0.01). The experimental-therapy group also had better metabolic control, as evidenced by lower glycohemoglobin values (7.2 +/- 0.7 vs. 10.8 +/- 1.2 percent; P less than 0.01). We conclude that suppression of endogenous insulin by intensive, continuous insulin treatment during the first two weeks after the diagnosis of IDDM may improve beta-cell function during the subsequent year.

A Prospective Study of the Development of Diabetes in Relatives of Patients with Insulin-Dependent Diabetes

BACKGROUND The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM), but the magnitude of the risk is unknown, as is the influence of other factors, such as age, sex, and race. METHODS From 1979 through 1989, we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies, as well as other factors. RESULTS Of the 4015 nondiabetic relatives, 125 (3.1 percent) had islet-cell antibodies in their initial serum samples, and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001), membership in a multiplex pedigree (P = 0.02), and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM, giving a relative risk of IDDM of 68 (95 percent confidence interval, 34 to 134) for antibody-positive relatives. Islet-cell-antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes. CONCLUSIONS Nondiabetic relatives of probands with IDDM who are in the first two decades of life, are members of multiplex pedigrees, and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves.

Lack of Immune Responsiveness to Bovine Serum Albumin in Insulin-Dependent Diabetes

BACKGROUND Epidemiologic studies have implicated the ingestion of cows milk in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Moreover, in a recent study, 100 percent of patients with new-onset IDDM had antibodies against bovine serum albumin (BSA), with a majority directed against a 17-amino-acid BSA peptide (ABBOS). Cellular immune mechanisms are thought to be the principal mediators of pancreatic beta-cell destruction in IDDM. METHODS We measured the responses of peripheral-blood mononuclear cells to BSA and ABBOS or serum IgG anti-BSA antibodies (by particle-concentration fluorescence immunoassay) in 71 patients with IDDM, 55 subjects at various degrees of risk for IDDM, 36 patients with other autoimmune disorders (chronic autoimmune thyroiditis, rheumatoid arthritis, and systemic lupus erythematosus), and 48 normal subjects. RESULTS The responses of peripheral-blood mononuclear cells to BSA or ABBOS were positive in 2 of 24 patients with new-onset IDDM, 1 of 25 first-degree relatives of patients with IDDM who were negative for islet-cell antibodies, 2 of 30 first-degree relatives of patients with IDDM who were positive for islet-cell antibodies, 1 of 28 patients with established IDDM, and 1 of 29 normal subjects. Similarly, anti-BSA antibodies were not detected significantly more often in patients with new-onset IDDM (3 of 31, 10 percent) than in normal subjects (1 of 37, 3 percent; P = 0.32). However, many patients with autoimmune disease and subjects at increased risk for IDDM had anti-BSA antibodies (frequency, 10 to 31 percent). CONCLUSIONS Anti-BSA antibodies may reflect a general defect in the process of immunologic tolerance associated with a predisposition to autoimmunity rather than immunity specific to beta cells. The absence of cellular immunity to BSA and ABBOS in IDDM does not support a role for this antigen in the pathogenesis of the disorder.

Type b insulin resistance in a 15-year-old white youth

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1259 GLYCOHEMOGLOBIN BY AFFINITY CHROMATOGRAPHY: A THIRTY MINUTE PROCEDURE IN CLINIC

The utility of glycohemoglobin (GHb) in the management of diabetes mellitus (DM) is undisputed. Clinical decisions frequently are deferred 3-5 days until the GHb results are available; hence, follow-up instructions must be given by telephone or letter. The delay and lack of personal attention may markedly reduce compliance; conversely, postponing new recommendations until the next evaluation may reduce the utility of GHb to a mere academic exercise. We evaluated affinity chromatography (AC) for the possibility of obtaining GHb results while the patients were in the clinic. From 23 children with insulin dependent DM, 25 ul of blood was collected by a fingerstick and GHb was measured by AC. Results for up to 5 specimens were available in 30 minutes. A venous blood specimen was collected simultaneously from the same 23 children and HbA1c was measured by high pressure liquid chromatography after removal of labile fraction (LF). A remarkable correlation was found between the two methods (r = 0.89). The study was repeated 2 months later and similar results were obtained (r = 0.91, n = 25). Even though LF was not removed in AC, the correlation between the two methods indicates that LF may only be an insignificant portion of total GHb. The AC was less expensive than the conventional methods and was more acceptable to the children as venipuncture was not required. We conclude that the utility of GHb may be improved in clinical practice utilizing AC, as prompt results can be obtained at less expense without the necessity of a venipuncture.

1231 IDIOPATHIC HYPERCALCIURIA (IH): A POTENTIAL CAUSE OF RENAL DISEASE IN CHILDREN WITH INSULIN DEPENDENT DIABETES MELLITUS (IDDM)

Renal disease is a common complication of IDDM. The pathogenesis is believed to be microvascular and to increase with duration of IDDM. Hypercalciuria causes renal dysfunction and has been reported in children with IDDM. A group of children (157) with IDDM had urine and blood collected after a 10 hour fast. Thirty-seven age similar non-diabetic (ND) subjects were controls. Urine calcium (Ca), phosphate (PO4) and creatinine (Cr) were measured. The Ca/Cr and PO4/Cr ratios were calculated as an indicator of urinary excretion. IH (definition: Ca/Cr 2 SD>mean for ND) was found in 45 (29%) of the IDDM subjects (6% prevalence in ND children). PO4/Cr in IDDM (1.2±0.06) was greater than ND (0.72±0.08) p<0.002. Ca/Cr correlated with PO4/Cr in subjects with IDDM while no relationship was found in ND. Ca/Cr correlated both with coincident serum glucose (r=0.34, p<0.001) and glycosylated hemoglobin (r=0.25 p<0.001) but was not related to duration of diabetes or the current insulin dose. Both Ca/Cr and PO4/Cr correlated inversely with serum PO4 in IDDM; serum PO4 correlated directly with PO4/Cr but was not related to Ca/Cr in ND. PTH levels in ND and IDDM children were normal.Conclusion:1) a defect in tubular reabsorption of Ca and P exists in IDDM that is related to blood glucose concentration; 2) the ion product of Ca3(PO4)2 in the urine of (29%) IDDM children exceeds the solubility constant and is 3 times that of the ND children; 3) IH may be a cause, previously unrecognized, of some renal complications of IDDM.

HYPERCALCIURIA AND GROWTH FAILURE IN CHILDREN WITH DIABETES

Growth failure and hypercalciuria have been noted independently in children with insulin-dependent diabetes mellitus (IDDM). We evaluated growth and calcium metabolism in 175 IDDM children and 38 non-diabetic (ND) sibs of similar ages. Height was determined by 2 of the authors using a Stadiometer. Blood and urine were collected in the AM before food and insulin had been taken. Results: (mean ± SEM) urine calcium/creatinine (Ca/Cr) (ND=0.13±.01, IDDM=0.21±.01 p<.001), serum Ca (ND=9.7±.07 mg/dl, IDDM=9.6±.02 mg/dl p=NS), alkaline phosphatase (ND=105.8±7.0 IU, IDDM 284.9±7.5 IU p<.001) Vitamin D3 ND=20.0±1.8 ng/ml, IDDM=23.0±2.0 ng/ml p=NS), PTH (ND=140.3±7.9 pg/ml, IDDM=158.4±5.2 p=NS), Ht (ND=54±3.8 percentile, IDDM=43.7±2.3 percentile p<.05). Ca/Cr correlated with coincident serum glucose r=.28 p<.0002, HbA1c r=.24 p<.0004, but not with serum Ca, alkaline phosphatase, vitamin D or PTH. Ca/Cr correlated inversely with Ht percentile r=.20 p<.01. IDDM with Ca/Cr>ND range were shorter 37±3.2 percentile than ND 54±3.8 percentile p<.01. Hypercalciuria was associated with both poor glycemic control and growth failure in IDDM children. When coincident serum glucose, HbA1c and duration of IDDM are factored out of the analysis of variance the Ca/Cr continues to have a negative correlation to height percentile. Hypercalciuria appears to be an important factor in the growth failure associated with IDDM.

GLYCOHEMOGLOBIN: COLORIMETRIC VS|[period]| CHROMATOGRAPHIC MEASUREMENT

Glycohemoglobin (GHb) is an indicator of long-term glycemic control. Fasting blood specimens were collected from 40 insulin-dependent diabetics. Patients measured fasting and 1 hour post-prandial blood glucose values on 2 days/wk. using a Dextrometer®. GHb was measured on each specimen in our laboratory after removing labile Schiff base (LSB) by high pressure liquid chromatography (HPLC) and a colorimetric method (CM) using thiobarbituric acid and in a commercial laboratory (CL) using mini columns without removing LSB. GHb measured by HPLC correlated better with CM (r=0.7) than with CL (r=0.49). This discrepancy was not explained by the presence of LSB as it was an insignificant component in HPLC results. Freezing the samples immediately increased HbAla+b but not HbA1c. Samples sent to CL were frozen at their request and may explain the discrepancy. When an aliquot of the specimens was stored at 25°C, 4°C or -20°C and GHb was measured at weekly intervals, results of CM remained stable while alteration occured in HPLC results. Fractions of Hb (A1a+b,A1c,A0) separated by liquid chromatography were collected. Ketoamine sugar was detected by CM in all fractions. Half of the total ketoamine sugar not measured by either HPLC or CL method was present in the HbA0 fraction. GHb measured by each of the 3 methods was compared to the mean blood glucose values during the preceding 4 wks. CM (r=0.53) correlated better than HPLC (r=0.25) or CL (r=0.3) with mean blood glucose values. GHb measured by CM more accurately predicts long-term glycemic control as it is less subject to handling artifacts and it represents the total GHb.