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In 1934 the Chicago physician R.T. Woodyatt suggested that 'The history of diabetes has been marked by recurrence of certain ideas which decline and disappear; only to go through a similar cycle again in an altered form in a new generation'. This has been particularly true of the concept of brittle diabetes which Woodyatt himself introduced in the 1930s. He never wrote a paper on the subject but contemporaries understood it to refer to excessive fluctuations of blood sugar which could not be explained by patient or physician errors; the cardinal feature was unpredictability and unexpected hypoglycaemic reactions. Also in the 1930s, practitioners of the newly formed psychosomatic movement took an interest in the effect of emotional factors on the course of diabetes and, in particular, patients who were 'difficult' or 'refractory'. What marked 'difficult' patients was that they did not follow their doctor's instructions or had recurrent diabetic ketoacidosis. By the 1950s the question was whether there were two distinct groups of patients; one whose lability could be cured by adjusting insulin, diet, and exercise, and another whose lability had an emotional origin. Did proponents of the organic school have patients (unreported) in whom lability had an obvious emotional cause or, conversely, were the psychosocial problems which the psychiatrists unearthed a consequence rather than a cause of the instability? My experience with a patient with factitious hypoglycaemia which remained undetected for weeks in a clinical research unit suggested that neither close observation nor screening by a psychiatrist could rule out factitious disease. Therefore in 1977 I suggested that the definition of brittle diabetes should be a patient whose life was 'constantly disrupted by episodes of hypo- or hyperglycaemia, whatever their cause'. This was widely accepted and there was a subtle shift towards regarding brittle diabetes as synonymous with recurrent ketoacidosis. In the 1980s two English and one American group investigated large series of such patients, using new methods to try to uncover a biochemical basis such as defective insulin absorption, accelerated degradation at insulin injection sites, and inappropriate secretion of various counterregulatory hormones. Most of these patients were young overweight women and the eventual conclusion was that in most the instability was self-induced. In the 1980s recurrent, often warningless, hypoglycaemia was recognized as a problem in its own right but in this new generation was reborn as a problem of insulin pharmacokinetics as Woodyatt originally conceived it.
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PMID:Brittle diabetes revisited: the Third Arnold Bloom Memorial Lecture. 904 86

The polyglandular autoimmune syndromes (PGA) are well known and are distinguished into type I, type II and type III. PGAI, also called APECED (autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy), is an autosomal recessive disorder, appearing in childhood and typically characterized by hypoparathyroidism (unusual in PGAII and PGAIII) and adrenal insufficiency. In APECED, autoimmune destruction of the pancreatic beta cells with development of insulin-dependent type 1 diabetes is possible, but less frequent than in the other PGAs, especially PGAII. The pathogenesis of this unique autoimmune disease is unknown. No HLA association seems to exist and genetic studies have assigned the autosomal APECED locus to chromosome 21. The case of a 28-years-old female suggesting the diagnosis of APECED, is presented, characterized by psycho-somatic abnormal development, teeth alterations, post-puberal gonadal failure with dystrophic hypoplasia of external genitalia, previous vaginal candidiasis, a slowly developing juvenile brittle diabetes. Intestinal malabsorption induced by Giardia lamblia occurred (probably resulting, like candidiasis, from immunological anergy). A strong familiarity linked to female sex was noticed (the mother, a sister, the little nice and some maternal female cousins being affected) while the father and a brother were healthy. Diabetes seems to be characterized by early onset and severe complications. In this patient no organo-specific antibodies were detected and the only immunologic disorder was a small decrease of CD3 and CD4/CD8 ratio, both CD4 and CD8 being at the lower normal range. This patient (and her female maternal relatives) needs a long-term follow-up in order to evaluate the function of endocrine glands and to initiate early treatment for hormonal deficits, as well as to detect the non-endocrine components of disease.
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PMID:[A rare case of juvenile diabetes mellitus associated with APECED (autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy) with strong X-linked familial inheritance]. 930 48

Insulin dependent diabetes mellitus is one of the most common metabolic diseases and affects 150,000 persons in France. To achieve good metabolic control requires a strict daily management of the treatment by the patients themselves. Lack of active involvement can have direct consequences which underlines the importance of a good adherence to the treatment. About 50% of the patients do not obtain adequate metabolic control. The major problem of insulin treatment consists in the repeated occurrence of severe hypoglycemias which may be accompanied by an alteration of the perception of hypoglycaemic signs. On the other hand, when the risk of severe hypoglycaemia is removed, glycosylated haemoglobin levels rise. Permanent hyperglycaemia leads to numerous somatical complications. An extremely dramatic combination of these two types of metabolic unbalance is represented by the brittle diabetes characterised by very frequent and extreme oscillations between hypo and hyperglycaemia. This raises the question of the influence of psychopathological factors on metabolic control and the possibility of improving metabolic control by acting on these factors. Epidemiological studies in diabetic patients have established higher prevalence rates of psychiatric disorders, in particular mood and anxiety disorders. The current prevalence rate of depression was found to be homogeneous in the literature about 11% and life time prevalence rates of major depressive disorders vary between 24% and 29%. The symptom profile of depression in diabetic patients is similar to that in depressed non diabetic psychiatric patients and it has been shown that highly sensitive psychiatric diagnosis of depression can be made among diabetic patients. There is no specific personality pattern in diabetic patients. There seems to be a relationship between metabolic control as defined by glycosylated haemoglobin and psychiatric disorders. Indeed, high levels of glycosylated haemoglobin are found in patients with psychiatric disorders. There seems to be some evidence of an association between blood glucose levels and actual emotional states. Nothing is known about the specificity of the link between psychiatric disorders and insulin-dependent diabetes mellitus. No study has evaluated if the relationship between psychiatric disorders and insulin-dependent diabetes mellitus is due to the disease itself or to the chronic feature of diabetes.
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PMID:[Insulin-dependent diabetes and psychiatric pathology: general clinical and epidemiologic review]. 945 27

There is little information on the clinical characteristics of "brittle" Type 1 (insulin-dependent) diabetic patients with predominantly hypoglycaemic instability. From a total cohort of 381 brittle diabetic patients from various parts of the United Kingdom, 64 (17%) had life-disrupting instability due to recurrent hospital admissions with hypoglycaemia. Compared to brittle patients with recurrent ketoacidosis (DKA), who comprised 59% of the total, those with recurrent hypoglycaemia were characterised by older mean age (34 +/- 20 v 22 +/- 11 y, p < 0.001), and more equal sex distribution (53% v 71% female, p < 0.05). Patients with "mixed brittleness" (24% of total) were intermediate between the other groups, in terms of both age and female predominance. Physicians in charge of patients with hypoglycaemic brittle diabetes considered psychosocial factors to be frequent underlying causes, though organic conditions such as lost hypoglycaemic warnings and alcohol abuse were also mentioned. Factitious insulin overdose was diagnosed in 3 patients. We conclude that hypoglycaemic brittle diabetes is a small but important sub-group of the overall brittle syndrome. It differs in age and sex distribution from the more common syndrome of recurrent DKA.
Diabetes Metab 1999 Sep
PMID:Brittle diabetes characterised by recurrent hypoglycaemia. 1056 19

Unstable and unpredictable disease control in diabetes or asthma, with frequent hospitalisations, is frequently referred to as 'brittle'. We describe two cases of Addison's disease with recurrent hospitalisations in hypo-adrenal crises. Both patients had significant psychosocial disruption, and failure to take hydrocortisone replacement therapy was admitted in one and biochemically proven in the other. We propose that 'brittle' Addison's disease in these cases was due to poor treatment compliance related to psychosocial factors. These features have particular similarities with the syndrome of brittle diabetes.
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PMID:Brittle Addison's disease: a new variation on a familiar theme. 1068 30

Integration of the patient's mental organization is an important part of all psychotherapeutic experiences. Generally, it is welcomed and thought well worth the effort needed to achieve it. However, there are some patients who feel terrified by this process. They seem to think that integration involves a loss of the self: they feel it is dangerous and even resist it with psychotic-type defenses. This was certainly the case for the patient described in this paper, who was affected from an early age by brittle diabetes. For her, this reaction was always activated by separation, and it also appeared prior to any developmental step she needed to take--e.g., in recognizing self-boundaries, sexual identity, and facing the oedipal conflict. On all these occasions her reaction was to run away from treatment in a state of deep regression, feeling suicidal, and liable to seriously harm herself through the mistreatment of her diabetes. The issue of integration, seen to arise with the concomitant loss of omnipotence, presents itself at different levels of development of the self and of the drives.
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PMID:The dread of integration. Integrative processes in a chronically ill borderline patient. 1074 37

Instability of glycemic levels is "normal" in type 1 diabetes, with different levels of severity, up to the restrictive definition of brittle diabetes (repeated ketoacidosis and/or severe hypoglycemias). Quantification of glycemic instability, in terms of intraday variability and day-to-day reproducibility, is advisable. Standard deviation of blood glucose, though a simple index does not discriminate between slow and brutal variations. Repartition of blood glucose values also only indicates dispersion. M values compares the patient values to an ideal blood glucose level, emphasizing the role of low values. The MAGE index measures the amplitude of the largest glucose excursions, thus evaluating appropriately glycemic variability. The Low Blood Glucose Index (LBGI) is a new index of variability emphasising (as the M value) the low glycemias. Each glycemia is given a value from O (if >=110 mg/dl) to 100 (if 20 mg/dl). It thus integrates the frequency and severity of hypoglycemias. According to its authors the LBGI would be the best indicator of severe hypoglycemias. The Mean of Daily Differences (MODD) evaluates the day-to-day reproducibility of blood glucose values. All the above indexes could easily be incorporated in the programmes of large memory glucose meters.
Diabetes Metab 2000 Apr
PMID:[How to measure glycemic instability?]. 1080 31

Islet transplantation offers the prospect of good glycemic control without major surgical risks. After our initial report of successful islet transplantation, we now provide further data on 12 type 1 diabetic patients with brittle diabetes or problems with hypoglycemia previous to 1 November 2000. Details of metabolic control, acute complications associated with islet transplantation, and long-term complications related to immunosuppression therapy and diabetes were noted. Insulin secretion, both acute and over 30 min, was determined after intravenous glucose tolerance tests (IVGTTs). The median follow-up was 10.2 months (CI 6.5-17.4), and the longest was 20 months. Glucose control was stable, with pretransplant fasting and meal tolerance-stimulated glucose levels of 12.5+/-1.9 and 20.0+/-2.7 mmol/l, respectively, but decreased significantly, with posttransplant levels of 6.3+/-0.3 and 7.5+/-0.6 mmol/l, respectively (P < 0.006). All patients have sustained insulin production, as evidenced by the most current baseline C-peptide levels 0.66+/-0.06 nmol/l, increasing to 1.29+/-0.25 nmol/l 90 min after the meal-tolerance test. The mean HbA1c level decreased from 8.3+/-0.5% to the current level of 5.8+/-0.1% (P < 0.001). Presently, four patients have normal glucose tolerance, five have impaired glucose tolerance, and three have post-islet transplant diabetes (two of whom need oral hypoglycemic agents and low-dose insulin (<10 U/day). Three patients had a temporary increase in their liver-function tests. One patient had a thrombosis of a peripheral branch of the right portal vein, and two of the early patients had bleeding from the hepatic needle puncture site; but these technical problems were resolved. Two patients had transient vitreous hemorrhages. The two patients with elevated creatinine levels pretransplant had a significant increase in serum creatinine in the long term, although the mean serum creatinine of the group was unchanged. The cholesterol increased in five patients, and lipid-lowering therapy was required for three patients. No patient has developed cytomegalovirus infection or disease, posttransplant lymphoproliferative disorder, malignancies, or serious infection to date. None of the patients have been sensitized to donor antigen. In 11 of the 12 patients, insulin independence was achieved after 9,000 islet equivalents (IEs) per kilogram were transplanted. The acute insulin response and the insulin area under the curve (AUC) after IVGTT were consistently maintained over time. The insulin AUC from the IVGTT correlated to the number of islets transplanted, but more closely correlated when the cold ischemia time was taken into consideration (r = 0.83, P < 0.001). Islet transplantation has successfully corrected labile type 1 diabetes and problems with hypoglycemia, and our results show persistent insulin secretion. After a minimum of 9,000 IEs per kilogram are provided, insulin independence is usually attained. An elevation of creatinine appears to be a contraindication to this immunosuppressive regimen. For the subjects who had labile type 1 diabetes that was difficult to control, the risk-to-benefit ratio is in favor of islet transplantation.
Diabetes 2001 Apr
PMID:Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. 1128 33

Disordered gastric motility occurs frequently in diabetes mellitus. Gastric emptying time is abnormal in about 50% of diabetic patients and delayed emptying time is known as an important cause for brittle diabetes in type 1 diabetes. We compared the rise in blood glucose after a standardized meal (oatmeal test) as a noninvasive screening test for diabetic gastropathy with the noninvasive measurement of gastric emptying time with ultrasound in type 1 and type 2 diabetic patients. The test result was considered pathological if the rise of blood glucose after an initial steady state did not reach 20 mg/dl in the first 20 min after the meal (prolonged blood glucose latency). We found a sensitivity of 90% (58.7-99.8) and a specificity of 100% (71.5-100) for the oatmeal test in type 1 diabetes in the gastropathy screening. In type 2 diabetes we found a sensitivity of 13% (1.5-38.3) and a specificity of 78% (60-90.7) (95% CI). In conclusion, the oatmeal test seemed to be a good, noninvasive screening test in diabetic gastropathy in type 1 diabetes, but has no diagnostic value in type 2 diabetes. The causes for such a difference may be due to a different postprandial blood glucose regulation in type 2 diabetes compared to the beta-cell-depleted type 1 diabetes.
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PMID:Postprandial blood glucose latency after oatmeal is a valid screening test for diabetic gastropathy in type 1 diabetes, but not in type 2 diabetes. 1133 Apr 3

Hyperglycemia is an important factor in the development and progression of the complications of diabetes. Pancreas transplantation is currently the only method able to achieve sustained normoglycemia in type I diabetes. By now, this procedure has become an accepted treatment option combined with kidney transplantation for selected patients with end-stage diabetic nephropathy. The definite benefits of pancreas transplantation comprise relieve from insulin administration, superb glycemic control, improved quality of life and long-term survival of patient with severe autonomic neuropathy. Presumed benefits represent stabilization or slowing of progression of microvascular complications. Definite disadvantages are the risk of the surgical procedure, graft rejection and the necessity of permanent immunosuppression. Isolated pancreas transplantation in nonuremic type-1 diabetic patients is still controversial. Diabetic complications of the potential recipient have to be potentially correctable by the transplantation and their significance must exceed all risks of the operation and life-long immunosuppression. Currently, approx. 25 combined transplants are performed per year in IKEM with the results comparable to those reported by the International Pancreas Transplant Registry. Seven nonuremic type-1 diabetic recipients of 8 operated in IKEM by June 2000 have been insulin-independent for 1-33 months. The main indication for isolated pancreas transplantation is brittle diabetes with hypoglycemia unawareness syndrome and labile diabetes with severe autonomic neuropathy and rapid progression of microangiopathy despite appropriate intensified insulin therapy.
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PMID:[Pancreas transplantation: who and when?]. 1137 22


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