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Intensive insulin treatment is defined by basal-prandial insulin therapy which tries to reproduce physiological insulin secretion. This requires 3 to 5 injections and self-monitoring of blood glucose 4 to 5 times a day. Patients who accept their disease and the demanding treatment regimen most often achieve HbA1(c) < 7.5%. Severe complications of diabetes can be avoided without increasing the risk of severe hypoglycemia. However, 50% of type 1 diabetic patients do not reach this objective. The reasons are: the disease itself, the diabetic patient, or the physician. Brittle diabetes with severe, repeated episodes of hypoglycemia and inversely persistent postprandial hyperglycemia prevents patients from reaching the ideal glycemic target. More often, the main obstacle is related to psychological problems: difficulties in self-regulation, denial of the disease, or phobia of hypoglycemia with avoidance behavior. Frequently, young women present eating disorders which can explain the poor diabetes control. The physician himself may be implicated in these poor glycemic results by not prescribing the right tools to obtain optimal glycemic control (staying with just two daily injections with premixed insulin) or by assigning glycemic targets inaccessible for the patient, or when an empathic relationship cannot be established between the patient and the physician. Patient empowerment is the key to the success of functional insulin treatment.
Diabetes Metab 2005 Sep
PMID:Limitations of the so-called "intensified" insulin therapy in type 1 diabetes mellitus. 1638 98

A 75-year-old man with type 1 diabetes and history of insulin therapy for previous 3 years using only human recombinant ones was suffering from unstable glycemic control. He had a high level of total insulin and a high titer of insulin antibodies (IA) (bound/total ratio: 89.8%). Low affinity constant (k(1): 0.0312 x 10(8) M(-1)) and high binding capacity (b(1): 51.8 x 10(-8) M) of IA in the patient detected by the Scatchard analysis were not compatible with those of IA associated with exogenous insulin injections in the diabetic patients, but compatible with those of the insulin autoantibodies found in patients with insulin autoimmune syndrome (IAS), although he had DRB1*0405, which may have protection against IAS development. The glucose infusion rate during hyperinsulinemic euglycemic clamp was 2.84 mg/kg/min, suggesting a high level of insulin resistance. Steroid pulse therapy (1000 mg for 3 days) aimed at reducing the possible effect of the IA on his insulin resistance and glycemic instability successfully decreased IA titer (from 89.8 to 58.3%), lowered its binding capacity (51.8-9.8 x 10(-8) M), increased glucose infusion rate (from 2.84 to 5.55 mg/kg/min) and improved glycemic control (HbA(1c): from 10.0 to 7.4%) with reduced blood glucose excursion. In conclusion, the alteration in insulin pharmacokinetics induced by IA seemed to be the cause of the brittle diabetes of the present case. Steroid treatment might be useful for the improvement of glycamic control in such patients with high IA levels and unstable blood glucose.
Diabetes Res Clin Pract 2006 Jun
PMID:A case of slowly progressive type 1 diabetes with unstable glycemic control caused by unusual insulin antibody and successfully treated with steroid therapy. 1643 34

Periodontal ligament (PDL) cells are the most important cells in the healing of wounds and the regeneration of periodontal tissues. The response of PDL cells regarding cellular activity to high glucose concentration levels could be the key in understanding the events associated with the dental care of brittle diabetes. We studied the effect of high glucose concentration levels on the cellular activity of PDL cells from five non-diabetic patients in vitro. PDL cells were cultured for 14 days in a normal glucose medium (1100mg/l of glucose) or in a high glucose medium (4500mg/l of glucose) and a 3-(4,5-dimethylithiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay for cellular viability was also performed. In order to evaluate the differentiation of PDL cells to osteoblast-like cells, mineralized nodule formation was induced with supplemented media containing 50microg/ml of ascorbic acid, 10mM of beta-glycerophosphate and 100nM of dexamethasone for 21 days. High glucose significantly inhibited the proliferation of PDL cells and reduced the optic density of the MTT assay. Concerning the mineralized nodule formation, the percentage of the calcified area to the total culture dish of PDL cells in high glucose level was lower than that in the normal glucose medium. In conclusion, high glucose inhibits the proliferation and differentiation of PDL cells. The data provide an explanation for the delayed periodontal regeneration and healing in diabetic patients.
Diabetes Res Clin Pract 2006 Oct
PMID:Effects of high glucose on cellular activity of periodontal ligament cells in vitro. 1681 98

Chronic inflammation plays an important role in the development of diabetes and its late complications. Over nutrition, physical inactivity, stress, truncal obesity, dyslipidaemia, hypertension and smoking directly and indirectly activate the family of nuclear factor kappa B, the principal factor of inflammatory response. Hiperglycaemia and especially brittle diabetes affect not only metabolic abnormalities but also modulate cell and humoral immune response. There is good evidence that looking for novel risk factors for development and progression of late diabetic complications among inflammatory markers are needed. Progress in the study on etiopathogenesis of micro- and macro-angiopathy have clinical implications.
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PMID:[The role of inflammation in the pathogenesis of late diabetic complications]. 1703 96

Type 1 diabetes is an intrinsically unstable condition. However, the term "brittle diabetes" is reserved for those cases in which the instability, whatever its cause, results in disruption of life and often recurrent and/or prolonged hospitalization. It affects 3/1000 insulin-dependent diabetic patients, mainly young women. Its prognosis is poor with lower quality of life scores, more microvascular and pregnancy complications and shortened life expectancy. Three forms have been described: recurrent diabetic ketoacidosis, predominant hypoglycemic forms and mixed instability. Main causes of brittleness include malabsorption, certain drugs (alcohol, antipsychotics), defective insulin absorption or degradation, defect of hyperglycemic hormones especially glucocorticoid and glucagon, and above all delayed gastric emptying as a result of autonomic neuropathy. Psychosocial factors are very important and factitious brittleness may lead to a self-perpetuating condition. The assessment of brittle diabetes requires quantification of the variability of blood glucose levels. To quantify instability, measures which have been developed, include Mean Amplitude of the largest Glycemic Excursions (MAGE), Mean Of Daily Differences (MODD), Lability Index (LI), Low Blood Glucose Index (LBGI), Clarke's score, Hyposcore, and continuous blood glucose monitoring. Once psychogenic problems have been excluded, therapeutic strategies require firstly, the treatment of underlying organic causes of the brittleness whenever possible and secondly optimising standard insulin therapy using analogues, multiple injections and consideration of Continuous Subcutaneous Insulin Infusion. Alternative approaches may still be needed for the most severely affected patients. Isolated islet transplantation (IIT), which restores glucose sensing, should be considered in cases of hypoglycaemic unawareness and/or lability especially if the body mass index is < 25, but with current immunosuppressive protocols patients must have normal renal function and preferably no plans for pregnancy. Implantable pumps have advantages for patients who either weigh more than 80 kgs or have abnormalities of kidney or liver function or are highly sensitised.
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PMID:Management strategies for brittle diabetes. 1707 32

Preemptive simultaneous kidney-pancreas transplantation (SKPT) was performed in two patients with Type 1 diabetes and nephrotic syndrome due to diabetic nephropathy, although the native kidneys exhibited near-normal function. Before and 3 months as well as 12 months after SKPT S-creatinine, creatinine clearance (Cr-Cl) and urinary protein excretion were measured. Additionally, 99mTC scintigraphic examinations of the kidneys were performed 3 and 12 months after SKPT. Thereby, the injected 99mTC activities were assessed in the kidney graft as well as in the patient's native kidneys. Aim of the study was to find out the impact of successful SKPT on proteinuria and further functioning of the patient's own kidneys after transplantation. Indication for pancreas transplantation was severe diabetic autonomic neuropathy and Brittle diabetes, respectively. In Patient 1, we registered 3 months after SKPT a near-normal protein excretion of mean 0.20 g/24-h urine at a Cr-Cl of 82 ml/ min. The scintigraphic examinations showed 60% of the radioactivity in the kidney graft and 40% in the patient's own kidneys (22% right and 18% left). Data 1 year after SKPT were: mean protein excretion 0.28 g/24-h urine, Cr-Cl 78 ml/min and in the scan, furthermore, 30% of the activity in the patient's native kidneys (16% right and 14% left). In Patient 2 after 3 months we obtained a mean protein excretion of 0.18 g/24-h urine at a Cr-Cl of 80 ml/min. Scintigram of the kidneys: 58% of the injected activity were measured in the kidney graft and 42% in the patient's own kidneys (22% right and 20% left). After 12 months of SKPT we measured a mean protein of 0.26 g/24-h urine and Cr-Cl 78 ml/min. Scintigram of the kidneys: 36% of the activity was in the patient's native kidneys (18% right and left). We conclude that in diabetic patients with nephrotic syndrome and near-normal function of the native kidneys SKPT leads to rapid and nearly complete diminution of proteinuria although the residual function of the patient's native kidneys was about 40% at 3 months after transplantation and slightly lower at 12 months after SKPT.
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PMID:Proteinuria disappears promptly after simultaneous kidney-pancreas transplantation in nephrotic diabetic patients with near-normal GFR. 1804 67

Accurate and reliable devices sensing glucose on a (near)-continuous basis may facilitate specific therapeutic adjustments that need to be made to avoid hypo- and hyperglycaemic excursions, thereby improving metabolic control. Current continuous glucose monitoring (CGM) systems indicate the glucose level, the direction and magnitude of change of glucose levels, and can be used to assess glycaemic variability. In addition, real-time CGM sensors can serve as a tool to predict impending glucose excursions, thereby providing alarm signals of hypo- and hyperglycaemic values warning the patient to take preventative actions. Quality of life may also improve by using CGM via reducing the fear of hypoglycaemia. Particularly patients with brittle diabetes, hypoglycaemia unawareness, gastroparesis, pregnant women, or pump users, who are motivated to participate in their diabetes care and are technologically adept, may benefit from CGM. However, to successfully implement CGM in daily practice, these devices must be accurate and reliable, and one must be aware of the limitations of current CGM systems, that originate from physiological and technical aspects. Whether CGM succeeds in improving metabolic control, reducing hypoglycaemic episodes, and improving quality of life in the majority of patients remains to be proven. Should this be the case, real-time CGM may reduce chronic diabetic complications, and avoid hospitalisations, thereby reducing health care costs. In this article we will review indications, advantages, limitations, clinical and technical aspects of current minimally-invasive and non-invasive CGM sensors.
Curr Diabetes Rev 2008 Aug
PMID:Minimally-invasive and non-invasive continuous glucose monitoring systems: indications, advantages, limitations and clinical aspects. 1869 Aug 96

Islet cell transplantation holds great promise for treating patients with type 1 diabetes mellitus (T1DM), and for preventing unstable metabolic state commonly refereed to as brittle diabetes in patients that undergo pancreatic resection given that it is a relatively noninvasive procedure and an attractive alternative to pancreas transplantation for restoring endogenous insulin secretion. The success of recent clinical trials for allogeneic islet transplantation as well as the increasing centers that perform auto-transplantation is showing that the beta cell replacement therapy for the treatment of patients with diabetes or total pancreatectomy has been firmly established. It needs only to be improved and made more widely available to the millions of desperate patients who search for alternatives to a life of insulin injections, hypoglycemia and the risks of end-organ damage. Steady progress has been achieved in recent years in different areas in the pancreatic islet transplantation process including islet cell processing, preservation, and immune therapies that justify optimism. To implement this therapeutic approach to larger cohorts of patients that would benefit from the restoration of beta cell function requires multiple interventions and the standardization of the different stages of islet transplant process. This article will review the possible areas of intervention and the ongoing research toward this important goal.
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PMID:Prospects for future advancements in islet cell transplantation. 1920 36

Type 1 diabetes currently affects 15,000 patients in Switzerland with a rising incidence worldwide. Pancreas or islet of Langerhans transplantation are alternatives to intensive insulin treatment, which decreases long-term complications at the cost of an increase of severe hyoglycemia. Pancreas transplantation, indicated mainly to diabetic patients with simultaneous kidney transplantation, has a high success rate, but is accompanied by high morbidity due to general surgery. Islet transplantation, a cell-therapy for type 1 diabetes, is in full development. It is mainly indicated as islet transplant alone in patients suffering from brittle diabetes, and is associated with a very low risk due to minimally invasive technique, but a lower rate of long-term success. New potential sources of beta cell replacement are beta-cell lines, stem cells and xenotransplantation.
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PMID:[Pancreas and islets of Langerhans transplantation: current status in 2009 and perspectives]. 1957 22

Devices that measure glucose on a near-continuous basis may provide a better insight into glycemic profiles, allowing patients with diabetes to make therapeutic adjustments to improve metabolic control, thereby reducing the risk of diabetic complications. Motivated and technologically adept patients with brittle diabetes, hypoglycemia unawareness, diabetic pregnancy, or who use pumps might benefit.Current evidence of continuous glucose monitoring (CGM) on health outcome in patients with diabetes is critically reviewed. No data are available on chronic complications or mortality. Therefore, surrogate endpoints need to be investigated, particularly HbA1c, number of hypo- and hyperglycemic episodes, time within normal, high, or low glucose concentrations, glycemic variability, and quality of life.Randomized controlled trials (RCTs) using CGM in a retrospective way did not show metabolic improvement. In contrast, most RCTs applying real-time CGM showed a decrease in HbA1c, reduced glycemic variability, and a diminished number and length of hypo- and hyperglycemic events. Using accurate, real-time CGM devices improves quality of life by reducing the fear of unexpected hypoglycemic events. These beneficial effects were observed despite the fact that in most studies no clear treatment algorithm based on CGM results was provided to the patients. However, most trials were too short in duration, with a variable use of CGM, and were performed in small study samples.In conclusion, real-time CGM systems can improve metabolic control, reduce hypoglycemic episodes, and improve quality of life. Whether this holds true for longer time periods and in the majority of patients remains to be proven. In the long term, CGM might help to reduce chronic diabetes complications and perhaps also mortality, thereby reducing health care costs.
J Diabetes Sci Technol 2008 Jul
PMID:A review of current evidence with continuous glucose monitoring in patients with diabetes. 1988 51


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