Andrew Muir

Preservation of C-peptide secretion in subjects at high risk of developing type 1 diabetes mellitus - A new surrogate measure of non-progression?

Abstract:  Individuals at high risk of developing type 1 diabetes mellitus can be identified using immunologic, genetic, and metabolic parameters. In the Diabetes Prevention Trial‐1 (DPT‐1), annual intravenous infusions of low doses of regular insulin, together with daily subcutaneous injection of a single low dose of Ultralente insulin at nighttime, failed to prevent or delay the onset of type 1 diabetes in high‐risk non‐diabetic relatives. In our study, we attempted to achieve β‐cell rest by administering higher doses of neutral protamine Hagedorn (NPH) insulin twice daily to high‐risk non‐diabetic subjects in an effort to prevent or delay the onset of the disease. The maximum tolerable dose was given with the dose reduced for any hypoglycemia (mean dose 0.33 ± 0.15; range 0.09–0.66 units/kg/d). We treated 26 subjects who were confirmed to have islet cell antibodies (ICAs) and a low first‐phase insulin response (FPIR) to intravenous glucose. Fourteen had normal glucose tolerance and 12 impaired glucose tolerance (IGT). The median duration of follow‐up was 5.5 yr. Diabetes occurred in 10 of 12 subjects with IGT and five of 14 subjects with normal glucose tolerance. The cumulative incidence of diabetes was the same as with that seen in a matched, observation group (subjects followed prospectively as part of the University of Florida natural history studies) (age, sex, ICA, insulin autoantibodies, duration of ICA prior to enrollment, FPIR, and glucose intolerance; p = 0.39), as was the rate of progression (p = 0.79). There was a higher rate of progression to diabetes in the group with abnormal glucose tolerance at baseline than in those with normal baseline glucose tolerance (p = 0.003). Interestingly, in non‐progressors, as opposed to progressors, there was no fall in C‐peptide (peak and area under the curve) production regardless of the type of tolerance testing (mixed meal, oral or intravenous) over time (p < 0.001). In this study, in the dose and regimen of NPH insulin used, insulin did not delay or prevent the development of type 1 diabetes. However, preservation of C‐peptide production in the prediabetic period appears to indicate non‐progression to clinical disease and may serve as a new surrogate for determining response to preventative efforts.

Autoimmune Addison's disease

Despite the introduction of therapeutic steroid hormone replacement in 1929, chronic adrenocortical insufficiency (Addisons disease) remains a potentially lethal condition with a significant morbidity. The institution of standard maintenance treatment is often insufficient to cover times of metabolic stress, so that mild, acute illnesses can be debilitating or even fatal if extra preventive measures are not taken. With the advent of improved public health measures and antibiotics, autoimmunity has replaced tuberculosis as the commonest cause of Addisons disease in developed nations. At least two in every three affected patients have an autoimmune basis for their disease, while most of the remainder arise from disseminated tuberculosis [9, 10, 19]. Rarer causes such as amyloidosis, metastatic neoplasia, lymphoma, non-tuberculous infection, hemorrhage, or adrenoleukodystrophy account for most of the remaining cases, but in many patients an identifiable cause for adrenal disease is never found. European epidemiologic studies report the prevalence of non-tuberculous Addisons disease as 3 6 per 100000 cases, while in New Zealand its incidence approximates 0.45 per 100000 per year [15, 32, 33]. Since the disease is so rare, many cases are not diagnosed until after death and, thus, mortality rates for patients suffering adrenal failure have not been accurately determined. Needless deaths continue to occur, however, because patients in Addisonian crisis are either misdiagnosed or inadequately resuscitated. Autoimmune Addisons disease does occur in isolation but more commonly it is part of an autoimmune polyglandular syndrome (APS, see the contribution by Bottazzo in this volume). Most patients are between ages 20 and 50 years at the time of onset. Females are reported to predominate among those patients who are diagnosed after age 30 years, but no sex bias exists among those with a younger age o f onset [22].

Intrafamilial and case-control association analysis of d2s152 in insulin-dependent diabetes

We have performed intrafamilial and case-control association studies to examine the previously reported linkage disequilibrium between D2S152 and a type 1 diabetes susceptibility gene on chromosome 2q31-q33 (IDDM7). Significant linkage disequilibrium was observed in our subset of 47 Florida affected sibpair families (p < 0.02) but not in the other 57 USA families. We were not able to detect any significant associations between IDDM and D2S152 using case-control studies in a Caucasian data set of 270 unrelated diabetic patients and 370 normal controls ascertained from Florida, or in a Chinese data set of 90 patients and 169 normal controls. Our results suggest that linkage disequilibrium between IDDM7 and D2S152 must be very loose.

Intervention Therapies for Insulin-Dependent Diabetes

Treatment of insulin-dependent diabetes remains problematic since there continues to be high rates of morbidity and mortality among affected patients. Good outcomes are most likely to be more common among patients who maintain endogenous insulin reserves for the longest time following diagnosis. The disease process can now be identified in its early, pre-symptomatic stages and thus, the time has come for the investigation of preventive therapies through multicenter clinical trials. A wide variety of strategies are available and their choice should be dependent on the pathogenic stage of disease at which treatment is initiated. This stage-specific approach to prevention is discussed with a particular focus on those therapies that will soon be tested in clinical trials.

Do doctors cause or prevent cerebral edema in children with diabetic ketoacidosis

Although cerebral edema occurs infrequently during the treatment of diabetic ketoacidosis (DKA), this unpredictable and often devastating complication is of such concern to pediatricians that they tailor treatments specifically to prevent it. Protocols that replace fluid deficit over 48 h and prolong the use of isotonic fluids to avoid rapid decline of serum osmolality have become the standards of care (1). Nonetheless, there is little experimental evidence to prove that these ‘conservative’ rehydration methods are safer than other rehydration regimens. Nor does epidemiologic evidence demonstrate a reduction of the incidence of cerebral edema because cautious rehydration protocols have become more widely used (2–4). This Hot Topic review will discuss papers that sought predictors of cerebral edema and those that assessed the pathogenic role of DKA therapy in the development of this complication.

Insulin Prophylaxis in Insulin-Dependent Diabetes Mellitus

All the experimental animal models of insulin-dependent diabetes mellitus (IDDM) and preliminary human trials suggest that insulin can be safely used not only for immediate therapeutic purposes but also in the prevention of the disease. The mechanism of protection induced by insulin prophylaxis may include both ‘β-cell rest’ and induction of immunoregulatory processes. Finally, combined therapies involving oral, subcutaneous and intravenous routes may be of potential advantage in disease prevention. Future studies will have to address these issues.

Prevention of insulin-dependent diabetes-1995.

Despite current treatment advances, insulin-dependent diabetes mellitus (IDD) is still associated with high morbidity and mortality, and with a huge financial burden both to the individual and society. Enhanced understanding of the natural history of the prediabetic period has made the disease predictable in both higher risk nondiabetic relatives and in the general population. Investigators around the world are now collaborating on three separate multicenter, randomized, controlled trials aimed at preventing the disease in at-risk individuals, engendering cautious optimism that the days are not too far away when IDD can safely be prevented.