Clinical Application of the Food Insulin Index for Mealtime Insulin Dosing in Adults with Type 1 Diabetes: A Randomized Controlled Trial.

BACKGROUND: The Food Insulin Index (FII) is a novel algorithm for ranking foods based on their insulin demand relative to an isoenergetic reference food. We compared the effect of carbohydrate counting (CC) versus the FII algorithm for estimating insulin dosage on glycemic control in type 1 diabetes. MATERIALS AND METHODS: In a randomized, controlled trial, adults (n = 26) using insulin pump therapy were assigned to using either traditional CC or the novel Food Insulin Demand (FID) counting for 12 weeks. Subjects participated in group education and individual sessions. At baseline and on completion of the trial, glycated hemoglobin A1c (HbA1c), day-long glycemia (6-day continuous glucose monitoring), fasting lipids, and C-reactive protein were determined. RESULTS: Changes in HbA1c from baseline to 12 weeks were small and not significant in both groups (mean ± SEM; FII vs. CC, -0.1 ± 0.1% vs. -0.3 ± 0.2%; P = 0.855). The incremental area under the curve following breakfast declined significantly among the FID counters with no change in the CC group (FID vs. CC, -93 ± 41 mmol/L/min [P = 0.043] vs. 4 ± 50 mmol/L/min [P = 0.938]; between groups, P = 0.143). The mean amplitude of the glycemic excursion (MAGE) was significantly reduced among the FID counters (FID vs. CC, -6.1 ± 1.0 vs. -1.3 ± 1.0 mmol/L; P = 0.003), and only the FID counters experienced a trend (-44% vs. +11%; P = 0.057) to reduced hypoglycemia. CONCLUSIONS: In a 12-week pilot study, MAGE and postprandial glycemia following breakfast were significantly improved with FII counting versus CC, despite no significant differences in HbA1c.

Comparison of antiemetics for nausea and vomiting of pregnancy in an emergency department setting.

OBJECTIVE: To compare time from medication administration to disposition from the Emergency Department (ED) between women treated for nausea and vomiting of pregnancy with different antiemetic agents. DESIGN: We performed a retrospective cohort study of women 13 weeks gestation or less treated in our Women and Infants Hospital ED for nausea and vomiting of pregnancy between 2009 and 2011. Data was collected on patient demographics, antiemetics used, and time to disposition. We analyzed time of administration of the antiemetic used first line (ondansetron versus metoclopramide versus promethazine or prochlorperazine) to time the discharge order was placed. RESULTS: We analyzed data from 439 women treated in the ED for nausea and vomiting of pregnancy. Forty-four percent received ondansetron alone, 47% received any other antiemetic alone, and 9% received more than one agent first line. Antiemetic agent selected did not differ by patient age, parity, current treatment for nausea and vomiting in pregnancy, orthostatics, ketonuria or disposition. We found no difference in time from medication administration to disposition between women who received ondansetron and women who received any other antiemetic (metoclopramide, prochlorperazine or promethazine). Adjusting for potential confounders, compared to patients who received any other first line therapy, patients who received ondansetron had 2.09 times the odds of having a time to disposition at or above the 75th percentile (95% CI 1.31-3.34). CONCLUSIONS: The use of ondansetron in the ED for nausea and vomiting of pregnancy was associated with similar mean time from administration to disposition as other antiemetics.

Improving the estimation of mealtime insulin dose in adults with type 1 diabetes: the Normal Insulin Demand for Dose Adjustment (NIDDA) study.

OBJECTIVE: Although carbohydrate counting is routine practice in type 1 diabetes, hyperglycemic episodes are common. A food insulin index (FII) has been developed and validated for predicting the normal insulin demand generated by mixed meals in healthy adults. We sought to compare a novel algorithm on the basis of the FII for estimating mealtime insulin dose with carbohydrate counting in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 28 patients using insulin pump therapy consumed two different breakfast meals of equal energy, glycemic index, fiber, and calculated insulin demand (both FII = 60) but approximately twofold difference in carbohydrate content, in random order on three consecutive mornings. On one occasion, a carbohydrate-counting algorithm was applied to meal A (75 g carbohydrate) for determining bolus insulin dose. On the other two occasions, carbohydrate counting (about half the insulin dose as meal A) and the FII algorithm (same dose as meal A) were applied to meal B (41 g carbohydrate). A real-time continuous glucose monitor was used to assess 3-h postprandial glycemia. RESULTS: Compared with carbohydrate counting, the FII algorithm significantly decreased glucose incremental area under the curve over 3 h (-52%, P = 0.013) and peak glucose excursion (-41%, P = 0.01) and improved the percentage of time within the normal blood glucose range (4-10 mmol/L) (31%, P = 0.001). There was no significant difference in the occurrence of hypoglycemia. CONCLUSIONS: An insulin algorithm based on physiological insulin demand evoked by foods in healthy subjects may be a useful tool for estimating mealtime insulin dose in patients with type 1 diabetes.

Ability of GHTD-amide and analogs to enhance insulin activity through zinc chelation and dispersal of insulin oligomers.

GHTD-amide is a tetrapeptide originally isolated from human urine that has hypoglycemic activity. Insulin occurs in secretory granules of beta cells as zinc-stabilized hexamers and must disperse to monomeric form in order to bind to its receptor. The aim of this study was to identify whether GHTD-amide and an analog called ISF402 (VHTD-amide) reduce blood glucose through enhancement of insulin activity by dispersing oligomers of insulin. Peptides containing the HTD-amide sequence and a free alpha-amino group were optimal at binding Zn(2+) and adopting secondary structure in the presence of Zn(2+). Binding was concentration dependent and resulted in a 1:1 Zn:peptide complex. In vitro the tetrapeptides dispersed hexameric insulin to dimers and monomers. GHTD-amide and ISF402 potentiated the activity of hexameric insulin when co-injected into insulin resistant Zucker rats. Injection of peptides with insulin caused reductions in blood glucose and C-peptide significantly larger than achieved with insulin alone, and serum insulin time profiles were also altered consistent with a reduced clearance or enhanced dispersal of the injected insulin. Insulin potentiation by ISF402 was reduced when lispro insulin, which does not form zinc-stabilized hexamers, was used in place of hexameric zinc insulin. In conclusion, GHTD-amide and ISF402 are zinc binding peptides that disperse hexameric insulin in vitro, and potentiate the activity of hexameric insulin more so than monomeric lispro insulin. These results suggest that dispersal of hexameric insulin through chelation of Zn(2+) contributes to the hypoglycemic activity of these tetrapeptides.

Antibodies against the CB10 fragment of type II collagen in rheumatoid arthritis.

Antibodies against intact type II collagen (CII) are a feature of rheumatoid arthritis (RA) but have limited diagnostic value. Here we assess whether either of the two major cyanogen bromide fragments of CII, namely CB10 or CB11, are more sensitive substrates for the detection of antibodies in RA. Cleavage of bovine CII with cyanogen bromide yielded CB10 and CB11; these were purified by column chromatography for use in an enzyme-linked immunosorbent assay. Serum antibodies were measured in patients with RA, psoriatic arthritis (PsA), osteoarthritis (OA) and blood donors. Results were compared with those using intact CII. Antibodies against CB10 were found in as many as 88% of 96 patients with long-standing RA, but only 12% of 33 patients with PsA, 6% of 34 patients with OA and 3% of 93 control sera. Lower frequencies for these diseases were obtained on testing for antibodies against CB11: 50%, 6%, 21% and 2%, respectively. The sensitivity of detection in RA of antibodies against CB10 compared with antibodies against intact CII (88% versus 24%) was not at the expense of specificity, which remained high at 94%. The much higher frequency of antibodies against CB10 in RA than in other rheumatic diseases or control sera indicates that CB10 is clearly a more sensitive substrate than the intact collagen molecule and, combined with other assays (rheumatoid factor, anti-cyclic citrullinated peptide [anti-CCP]), might comprise a panel with a highly reliable predictive value. Moreover, our findings should encourage renewed interest in the role of collagen autoimmunity in the pathogenesis of RA.

An arthritogenic monoclonal antibody to type II collagen, CII-C1, impairs cartilage formation by cultured chondrocytes.

Antibodies to type II collagen (CII) cause articular damage in collagen-induced arthritis (CIA) in mice as judged by passive transfer to naive animals of mAb to CII. We tested the hypothesis that mAb degrade cartilage structure by reacting with functionally important regions of the collagen molecule by examining the effects of an arthritogenic mAb to CII, CII-C1, on cultured bovine chondrocytes at high density, at days 7 and 14. The effects were compared of CII-C1, an isotype-matched control mAb, or medium alone, on chondrocyte proliferation and viability, cell morphology, matrix structure by light and electron microscopy, and matrix synthesis by metabolic labelling with 3H-proline for collagen or 35SO4 for proteoglycans. Chondrocytes in culture remained viable, proliferated, and produced an extracellular matrix in which CII was the major collagen. The addition of CII-C1, but not a control mAb, increased the synthesis of CII and proteoglycan, and caused disorganization of the extracellular matrix and thin collagen fibrils ultrastructurally. Moreover, using a cell-free assay, CII-C1 inhibited the normal self-assembly of collagen fibrils from CII in solution. The finding that the mAb to CII, CII-C1 has striking degradative effects in vitro on cartilage synthesis suggests that antibodies to collagen perpetuate the chronic phase of CIA and that, in mice at least, such antibodies are an important component of pathogenesis.

Measurement of antibodies to collagen II by inhibition of collagen fibril formation in vitro.

Antibodies to type II collagen (collagen II) are pathogenic in experimental collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis (RA). Hitherto, results of assays for anti-collagen II have proven to be inconsistent. We tested whether mouse monoclonal antibodies (mAbs) to collagen II inhibit the natural self-assembly of soluble triple-stranded collagen II monomers to form insoluble polymeric fibrils. A spectrophotometric assay of self-assembly was based on change in absorbance at 313 nm, observed over 0-60 min after neutralisation and warming of a solution of monomeric collagen II. Two mAbs to collagen II (CII-CI and M2.139) strongly inhibited self-assembly of collagen II but not collagen I, whereas another antibody, CII-F4, and an irrelevant control mAb did not. Notably, CII-CI and M2.139, but not CII-F4, induce arthritis on passive transfer to naïve mice. The arthritogenic effects of mAbs CII-CI and M2.139 in vivo, and inhibition of collagen II self-assembly in vitro, may be attributable to interference with critical epitopes at sites essential for the stabilisation of the mature polymeric collagen II fibril, and, hence, the integrity of the entire cartilage matrix. This assay for inhibition of self-assembly of collagen II could be developed for routine measurement of anti-collagen II in body fluids as a marker of early RA, and perhaps also to distinguish populations of antibodies to collagen II that either have or lack the capacity to perpetuate arthritis.

A diabetes-related epitope of GAD65: a major diabetes-related conformational epitope on GAD65.

The 65-kDa isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes, and most patients have serum antibodies reactive with conformational epitopes on the GAD65 molecule. The aims of this study were to prepare mutants of GAD65 to further localize the type 1 diabetes epitope in the region of the PEVKEK loop of GAD65 and to identify the particular amino acids within the epitope that are recognized by autoimmune diabetes sera.