Management Of Insulin-dependent Diabetes Mellitus Research Articles

Insulin Derived Fibrils Induce Cytotoxicity in vitro and Trigger Inflammation in Murine Models.

Effective exogenous insulin delivery is the cornerstone of insulin dependent diabetes mellitus management. Recent literature indicates that commercial insulin-induced tissue reaction and cellular cytotoxicity may contribute to variability in blood glucose as well as permanent loss of injection or infusion site architecture and function. It is well accepted that insulin formulations are susceptible to mechanical and chemical stresses that lead to insulin fibril formation. This study aims to characterize in vitro and in vivo toxicity, as well as pro-inflammatory activity of insulin fibrils. In vitro cell culture evaluated cytotoxicity and fibril uptake by macrophages and our modified murine air-pouch model quantified inflammatory activity. The latter employed FLOW cytometry and histopathology to characterize fibril-induced inflammation in vivo, which included fibril uptake by inflammatory phagocytes. These studies demonstrated that insulin derived fibrils are cytotoxic to cells in vitro. Furthermore, inflammation is induced in the murine air-pouch model in vivo and in response, macrophages uptake fibrils both in vitro and in vivo. Administration of insulin fibrils can lead to cytotoxicity in macrophages. In vivo data demonstrate insulin fibrils to be pro-inflammatory which over time can lead to cumulative cell/tissue toxicity, inflammation, and destructive wound healing. Long term, these tissue reactions could contribute to loss of insulin injection site architecture and function.

Kidney Pancreas Transplant, a Brief Comprehension to Care

Surgical treatments for Insulin Dependent Diabetes Mellitus (IDDM) complicated with Advanced Chronic Kidney Disease (CKD) have emerged with the hope of providing a better sustainable quality of life. This article aims to highlight the utility of kidney and pancreas transplant in the management of IDDM with renal failure. There are different surgical methodologies, of which Simultaneous Pancreas And Kidney Transplantation (SPK) has been the most promising; in terms of graft survival and decreasing the need for a second surgical intervention in terms of kidney transplant. However, long waiting lists to find matching donors and post-operative complications are the most challenging obstacles. All recipients shall be screened for anti-HLA antibodies, non-HLA antibodies and Coronary Heart Disease (CHD). The presence of CHD poses a mortality risk post-surgery. Recipient selection requires a meticulous insight based on the insulin requirements, with the fact that not all will achieve insulin independence. A donor’s risk factors must be estimated by the Pancreas Donor Risk Index (PDRI), the higher the score lower the chances of graft survival. Pancreatic graft failure has no unanimously agreed definition of rejection and is dependent on a variety of donor and recipient factors. Close follow up and a high index of suspicion for any unexplained signs or symptoms is required to detect early allograft rejection, and the consideration of other surgical and medical etiologies is also required. This mini review will discuss various options for the management of insulin dependent diabetics whose diabetes remain uncontrolled with maximal efforts and have developed advanced chronic kidney disease pending renal replacement.

Pathological consequences of C-peptide deficiency in insulin-dependent diabetes mellitus.

Diabetes is associated with several complications such as retinopathy, nephropathy, neuropathy and cardiovascular diseases. Currently, insulin is the main used medication for management of insulin-dependent diabetes mellitus (type-1 diabetes). In this metabolic syndrome, in addition to decrease of endogenous insulin, the plasma level of connecting peptide (C-peptide) is also reduced due to beta cell destruction. Studies in the past decade have shown that C-peptide is much more than a byproduct of insulin biosynthesis and possess different biological activities. Therefore, it may be possible that C-peptide deficiency be involved, at least in part, in the development of different complications of diabetes. It has been shown that a small level of remaining C-peptide is associated with significant metabolic benefit. The purpose of this review is to describe beneficial effects of C-peptide replacement on pathological features associated with insulin-dependent diabetes. Also, experimental and clinical findings on the effects of C-peptide on whole-body glucose utilization, adipose tissue metabolism and tissues blood flow are summarized and discussed. The hypoglycemic, antilipolytic and vasodilator effects of C-peptide suggest that it may contribute to fine-tuning of the tissues metabolism under different physiologic or pathologic conditions. Therefore, C-peptide replacement together with the classic insulin therapy may prevent, retard, or ameliorate diabetic complications in patients with type-1 diabetes.

Haemodynamic consequences of recurrent insulin-induced hypoglycaemia

1. Recurring insulin-induced hypoglycaemia (RIIH) often occurs during the therapeutic management of insulin-dependent diabetes mellitus. Controversy currently exists in the literature as to the ability of insulin and/or hypoglycaemia to promote hypertension. Could insulin and/or hypoglycaemia promote adverse pressor effects? If so, under what conditions and through what mechanism? Thus, the present study was performed to evaluate the hypothesis that RIIH produces hypertension via induction of heme oxygenase (HO)-1, promoting a significant increase in endogenous carbon monoxide (CO). 2. Male Sprague-Dawley rats were treated for 2 weeks with varying doses of insulin (1, 3, 5, 7 and 9 U/kg, s.c.) or vehicle and fed normal rat chow or a zinc diet (1 mmol/L) for 2 weeks. Tail-cuff blood pressure, food intake and blood glucose states were monitored daily. 3. A dose-dependent decrease in blood glucose was observed in insulin-treated rats. Blood pressure was significantly elevated in rats treated with 9 and 7 U/kg insulin compared with those treated with other doses of insulin. However, there was no change in urine output among the groups. Feeding of a high-zinc diet to rats treated with 7 U/kg insulin and treatment with the HO-1 inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG; 20 mg/kg) after insulin injection resulted in a significant reduction in blood pressure compared with 7 U/kg insulin injection alone. In addition, HO-1 protein levels in the heart and kidney and endogenous CO levels were reduced in 7 U/kg insulin-treated rats fed the high-zinc diet compared with those treated with the same dose of insulin alone. 4. The results of the present study demonstrate that RIIH promotes hypertension and that restoration of normal CO levels with a high-zinc diet and ZnDPBG reduces blood pressure.

A Synthetic Approach Toward a Self‐Regulated Insulin Delivery System

Stimuli-responsive “smart gels” that undergo physicochemical property changes in response to external stimuli can provide both a functional and structural basis for selfregulated materials and systems. Of particular interest are those materials sensitive to chemical stimuli, that is, the fluctuation in the concentration of specific biomolecules, that can mimic biofeedback systems, thus providing many attractive platforms for biomedical applications. Glucose has been a molecule of interest for decades owing to its relevance to the treatment of diabetes. Diabetes is not an infectious disease, but its rapidly increasing worldwide prevalence has been recognized as a pandemic, and thus diabetes poses a serious global health threat much like epidemics of truly infectious diseases, such as HIV/AIDS. Despite the necessity for the continuous and accurate glycemic control in the management of insulin-dependent diabetes mellitus (IDDM), the current palliative treatment relies almost solely on the patients self injection of insulin; this self injection not only impinges on the quality of life of the patient but also fails to precisely control the dose of insulin, where an overdose must be strictly avoided as it causes serious hypoglycemia. For the preparation of self-regulated insulin delivery systems, the following two approaches have historically prevailed. One is based on enzymatic reactions between glucose oxidase (GOD) and glucose, a similar rationale to those exploited in commercial glucose sensors. The other type utilizes carbohydrate-binding lectin proteins, such as concanavalin A (Con A), as a complementary binder to glucose. These protein-based materials eventually denature and lose activity, and thus are not practical for long-term use and storage. Another problem is the strong cytotoxicity of Con A; this cytotoxicity has, thus far, prevented any clinical applications of these materials. Herein we describe a totally synthetic alternative to these materials. Phenylboronic acid (PBA), a synthetic molecule capable of reversibly binding with 1,2or 1,3-cis-diols including glucose, is utilized as the molecular basis. Our previous studies have shown that the glucose-dependent shift in the equilibrium of PBA between the uncharged and anionically charged forms, when coupled with a properly amphiphilic three-dimensional backbone (or gel), could induce a reversible change in the volume of the gel. The resultant abrupt and rapid change in the hydration, under certain conditions, could cause a localized dehydration of the gel surface, that is, a so-called skin layer, thus offering a method to instantly control the permeation of gel-loaded insulin. This goal is a great challenge and relies on achieving sufficient glucose sensitivity under physiological pH and temperature, that is, pH 7.4 and 37 8C, while also fine tuning the system so it shows a gated response to the change in glucose concentration critically at the level of normoglycemia, i.e., ca. 1 gl . To achieve this goal, we have systemically explored the structure–property correlation by focusing on (meth)acrylamide-based hydrogels. The major efforts have been directed to controlling the apparent pKa of PBA; the pKa depends not only on chemical structure of PBA, but also on the state of hydration. To make the situation more complicated, in a hydrogel environment the degree of hydration is a function of (as well as temperature, ionic strength, pH, and sugar concentration) the hydrophilicity, rigidity, and density of the main chain components and the amount of PBA. Herein we describe a gel that meets all the above criteria; the chemical structure of this gel turned out to be a remarkably simple copolymer system. A smart gel has been shown to act as an artificial pancreas under conditions closely related to human glucose homeostasis. As illustrated in Figure 1a, PBA derivatives in water exist in equilibrium between uncharged (i) and anionically charged (ii) forms. Upon addition of glucose, only the charged PBA (ii) can form a stable complex with glucose (iii), and the formation of this complex results in an apparent decrease in the amount of anionically charged PBA (ii). On consumption of the phenylboronate (ii), the equilibrium between (i) and (ii) shifts toward the latter (ii). Since the complexed PBA (iii) is also anionically charged, further addition of glucose leads to a shift in the equilibrium (i + ii + iii) toward the phenylboronate anions (ii + iii), and a decrease in the amount of [*] Dr. A. Matsumoto, J. Nishida, Dr. H. Matsumoto, Dr. Y. Miyahara Institute of Biomaterials and Bioengineering Tokyo Medical and Dental University Kanda-surugadai 2-3-10, Chiyoda-ku, Tokyo 101-0062 (Japan) E-mail: miyahara.bsr@tmd.co.jp Dr. T. Ishii Department of Bioengineering, The University of Tokyo Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8656 (Japan)

Adaptation of Glucokinase Gene Expression in the Rat Dorsal Vagal Complex in a Model for Recurrent Intermediate Insulin-Induced Hypoglycemia: Impact of Gender

Standard therapeutic management of insulin-dependent diabetes mellitus with intermediate-acting insulin poses a significant risk for iatrogenic hypoglycemia and associated hypoglycemia-associated autonomic failure. Gender differences in preservation of counterregulatory function during recurring hypoglycemia have been documented in the clinical setting. In rats, repeated induction of prolonged hypoglycemia by neutral protamine Hagadorn insulin (NPH) results in diminished neuronal transcriptional activation in several key metabolic loci in male, but not female rat brain, including the hindbrain dorsal vagal complex (DVC). Glucose is committed to glycolytic catabolism by hexokinase-mediated phosphorylation. The low-affinity, high K (m) hexokinase, glucokinase (GCK), monitors intracellular glucose levels in pancreatic beta cells, and is purported to fulfill a similar function in the CNS. GCK is expressed in the rat DVC, where mRNA is localized to neurons that exhibit electrophysiological sensitivity to glucose imbalance. The current study investigated the hypothesis that DVC GCK gene expression acclimates to RIIH in a gender-dependent manner. Quantitative real-time RT-PCR was used to evaluate GCK mRNA levels in microdissected DVC tissue obtained from male and female rats before or after one or serial doses of NPH. Basal DVC GCK transcripts were equal between ovariectomized (OVX) female rats implanted with estradiol benzoate (EB) or oil (O). Tissue mRNA levels were increased following a single NPH injection in both groups, but this response was greater in the presence of estrogen. Basal GCK gene expression was elevated by precedent insulin dosing in both O- and EB-implanted rats; however, transcripts were not modified relative to this adjusted baseline during subsequent NPH treatment in either group of females. While acute NPH treatment did not modify tissue transcript levels in orchidectomized (ORDX) or sham-ORDX rats, precedent NPH dosing increased basal GCK mRNA levels and further enhanced gene expression during ensuring hypoglycemia in sham males. These studies provide novel evidence for gender-dimorphic DVC GCK gene responses to single and serial intermediate-acting insulin administration. Further research is required to determine if and how stimulatory versus inhibitory transcriptional adaptation of this gene profile in male and female rats, respectively, impacts glucose-sensing functions in the DVC, and whether such adjustments may contribute to gender differences in magnitude of precedent hypoglycemic impairment of counterregulation.

Recurrent insulin-induced hypoglycemia causes site-specific patterns of habituation or amplification of CNS neuronal genomic activation

Antecedent hypoglycemia is a primary factor in hypoglycemia-associated autonomic failure, a pathophysiological condition characterized by impaired glucose counterregulatory function. Conventional therapeutic strategies involving administration of intermediate dosage-release formulations of insulin in the management of insulin-dependent diabetes mellitus result in frequent iatrogenic hypoglycemia. This study investigated the neuroanatomical location, direction, and magnitude of CNS neuronal genomic activation by singular versus repeated induction of hypoglycemic bouts of greater than 6 h duration achieved by administration of the intermediate-acting insulin, humulin neutral protamine Hagedorn (NPH). Adult male rats injected subcutaneously with Humulin NPH exhibited robust immunolabeling for the nuclear transcription factor, Fos, in discrete telencephalic, diencephalic, midbrain, and caudal hindbrain loci in a pattern that was not identical to that described for regular insulin. Administration of four doses of insulin on as many days significantly diminished or extinguished Fos immunostaining within the parvocellular hypothalamic paraventricular nucleus, lateral hypothalamic area, dorsomedial hypothalamic nucleus, thalamic paraventricular nucleus, nucleus tractus solitarius, and area postrema, but did not modify labeling of other metabolic loci. However, numbers of Fos-immunoreactivity-positive magnocellular neurons in the hypothalamic paraventricular and supraoptic nuclei were significantly increased after the second and fourth insulin doses, relative to the single-dose group. Concurrent observations of exacerbated hypoglycemia and modified patterns of glucoregulatory hormone secretion after serial injections of intermediate-acting insulin suggest that central mechanisms governing compensatory endocrine responses, specifically glucagon, become habituated to repetitive hypoglycemia of extended duration. Resultant alterations in CNS-islet and -adrenomedullary output and hypothalamic–pituitary–adrenal activity may reflect diminished neuronal activation within one or more of the brain loci characterized here by nonuniform transcriptional activation. The current studies provide a neuroanatomical foundation for further investigation of the neurochemical phenotypes and interconnectivity of functionally adaptive neurons, underlying cellular and molecular mechanisms of diminished or enhanced activation, as well as the impact of these modified cellular responses on glucose counterregulation during administration of intermediate-acting insulin.

A telemedicine support for diabetes management: the T-IDDM project

In the context of the EU funded Telematic Management of Insulin-Dependent Diabetes Mellitus (T-IDDM) project, we have designed, developed and evaluated a telemedicine system for insulin dependent diabetic patients management. The system relies on the integration of two modules, a Patient Unit (PU) and a Medical Unit (MU), able to communicate over the Internet and the Public Switched Telephone Network. Using the PU, patients are allowed to automatically download their monitoring data from the blood glucose monitoring device, and to send them to the hospital data-base; moreover, they are supported in their every day self monitoring activity. The MU provides physicians with a set of tools for data visualization, data analysis and decision support, and allows them to send messages and/or therapeutic advice to the patients. The T-IDDM service has been evaluated through the application of a formal methodology, and has been used by European patients and physicians for about 18 months. The results obtained during the project demonstration, even if obtained on a pilot study of 12 subjects, show the feasibility of the T-IDDM telemedicine service, and seem to substantiate the hypothesis that the use of the system could present an advantage in the management of insulin dependent diabetic patients, by improving communications and, potentially, clinical outcomes.

What's new: newly approved drugs for children.

1. Myles B. Abbott, MD* 2. Robert H. Levin, PharmD† 1. 2. *Private pediatric practice in Berkeley and Orinda, CA, and Clinical Professor of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA. Dr. Abbott is a consultant for Express Scripts. 3. 4. †Professor of Clinical Pharmacy, University of California San Francisco School of Medicine, San Francisco, CA. Dr. Levin has funding for two pharmacy specialty residents from Bristol-Meyers-Squibb. In 2000, the United States Food and Drug Administration (FDA) approved 160 medications and medical devices, many that have pediatric indications. We discuss eight of these medications that have clinical importance to the general pediatrician. Two of the medications are new drugs (Table 1⇓ ), three represent new delivery systems for existing drugs (Table 2), and three are new combinations of drugs (Table 3)⇓ . View this table: Table 1. Newly Approved Drugs View this table: Table 2. New Delivery Systems View this table: Table 3. New Drug Combinations ### Lantus™ Lantus (insulin glargine, Aventis, Parsippany, NJ) is a long-acting recombinant human insulin analog indicated for the management of insulin-dependent diabetes mellitus. It has a relatively constant glucose-lowering profile without peaks and valleys over 24 hours, allowing it to be administered once every 24 hours. It may be best suited as a substitute for patients receiving twice-daily intermediate-acting insulin, for those experiencing the“ dawn phenomenon” with an intermediate-acting insulin, or for those who experience hypoglycemia from intermediate- or long-acting insulins. It is approved for use in children 6 years of age and older and is administered subcutaneously, usually at bedtime. Children currently using once-daily intermediate- or long-acting insulins can be changed to the same dose of insulin administered as Lantus. When initiating therapy for children currently receiving twice-daily intermediate-acting insulin, the dose should be 80% of the total daily dose of the intermediate-acting insulin to prevent hypoglycemia. Close glucose monitoring is vital during the change in therapy. Lantus cannot be mixed with any other type of insulin, including …

Level of Knowledge and Self-Care in Diabetics in a Community Hospital in Najran

Level of Knowledge and Self-Care in Diabetics in a Community Hospital in Najran

Eating disorders and adolescent diabetes: is there a link?

Issues commonly associated with normal adolescent development can affect the management of insulin-dependent diabetes mellitus, and similarities between psychosocial issues relating to diabetes and eating disorders have been suggested. This article discusses the issues and the problematic coexistence of eating disorders and diabetes in adolescence. The aetiology of eating disorders is multifactorial, and this article explores whether the existence of diabetes in adolescence potentially increases susceptibility to the development of eating disorders. Finally, the authors suggest ways in which paediatric nurses can approach the care of adolescents with coexisting diabetes and eating disorders.

Parent–child relationships and insulin-dependent diabetes mellitus: Observational ratings of clinically relevant dimensions.

An observational measure of parent-child relationships was developed based in family systems theory and used to predict the management of insulin-dependent diabetes mellitus (IDDM). The new measure reliably assessed interactions between 74 parents and their school-age and adolescent children with IDDM in this multitrait, multimethod study. The observational measure predicted both ratings of adherence to treatment and biological indices of metabolic control (glycosylated hemoglobin). Diabetes was better maintained in children whose parents were more emotionally supportive, had better resolved their grief about their child's diabetes, were less sad and angry, and in parent-child dyads were better able to resolve conflicts.

Newman's theory and insulin dependent diabetes mellitus in adolescence.

Application of Margaret Newman's theory of Health as Expanding Consciousness is presented as beneficial for both the school nurse and the adolescent with Insulin Dependent Diabetes Mellitus (IDDM). The tenets of Newman's theory are reviewed and application drawn to adolescent development, the management of IDDM, and the development of an Individualized Healthcare Plan (IHP). Implications of the theory for school nurse case management and the process of identifying an adolescent's meaning of health are explored.

Cost-effectiveness of Intensive Insulin Therapy in the Diabetes Control and Complications Trial

<h3>To the Editor.</h3> —The Diabetes Control and Complications Trial (DCCT) Research Group¹has recently published data that suggest that intensive insulin therapy for management of insulin-dependent diabetes mellitus (IDDM) may be well within the range of cost-effectiveness considered to represent good value. The DCCT group needs to be commended for such a thorough analysis and for providing yet another dimension to our understanding of the public health aspects of diabetes. Economic analysis alongside randomized clinical trials offer another important perspective to trial findings and can provide a rational means of assessing the implications of translating research information into practice. Given the importance of this study, it would be useful to have the insights of the authors regarding 3 aspects of the analysis. First, while clinical trials may offer data that are internally valid, they are often not readily generalizable—an issue that may be particularly important when it comes to

PSYCHOLOGICAL FACTORS IN INTENSIVE MANAGEMENT OF INSULIN-DEPENDENT DIABETES MELLITUS

With the publication of the DCCT results in 1993, hope has been given to patients with type I diabetes that blindness, kidney failure, and neuropathies are not necessarily what awaits them. However, to assume that diabetes is simply a disease that can be controlled "if only the patient would be compliant" is an incredibly naive way to approach treatment. Practitioners need to be keenly aware of not only the complexities of intensive management of type I diabetes but perhaps more importantly the numerous psychological factors that determine whether treatment adherence will occur. Psychological issues such as patient perceptions of symptoms, fear, unawareness of symptoms because of autonomic dysregulation or cognitive decline, attitudes, and control issues need to be assessed. These issues can be assessed quite easily with questionnaires, scales, and interview schedules readily available to practitioners. Additionally, for those patients who may not be attuned to monitoring physiologic or cognitive cues, awareness training and other coping skills interventions are available that can be incorporated into existing diabetes education programs. A mutual effort by the patient and health-care provider team can lead to success in intensive management of IDDM.

Lifetime benefits and costs of intensive therapy as practiced in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group

To examine the cost-effectiveness of alternative approaches to the management of insulin-dependent diabetes mellitus (IDDM).A Monte Carlo simulation model was developed to estimate the lifetime benefits and costs of conventional and intensive insulin therapy. Data were collected as part of the Diabetes Control and Complications Trial (DCCT) and supplemented with data from other clinical trials and epidemiologic studies.Twenty-nine academic medical centers.Persons with IDDM in the United States who meet demographic and clinical eligibility criteria for enrollment in the DCCT.Conventional vs intensive diabetes management.Approximately 120 000 persons with IDDM in the United States meet DCCT eligibility criteria. Implementing intensive rather than conventional therapy in this population would result in a gain of 920 000 years of sight, 691 000 years free from end-stage renal disease, 678 000 years free from lower extremity amputation, and 611 000 years of life at an additional cost of $4.0 billion over the lifetime of the population. The incremental cost per year of life gained is $28 661.Over a lifetime, DCCT-defined intensive therapy reduces complications, improves quality of life, and can be expected to increase length of life. From a health care system perspective, intensive therapy is well within the range of cost-effectiveness considered to represent a good value.

Caring for the adolescent diabetic.

The management of insulin-dependent diabetes mellitus is a challenge for the adolescent patient, his/her family and the health-care team supporting them. If treatment is to be successful and the longer-term complications of diabetes averted or delayed, nurses need to understand the various psychological and physiological factors that contribute to the difficulties in maintaining glycaemic control during this life stage. This article examines some of these factors with a view to encouraging nurses to adopt strategies that will improve patient confidence and coping skills in diabetic care.

New developments in treating children with insulin-dependent diabetes mellitus

A number of new developments in the management of insulin-dependent diabetes mellitus have occurred in the past several years. Primary care providers including pediatric nurse practitioners need to be aware of these developments so that they can work effectively with specialty providers in caring for children with insulin-dependent diabetes mellitus. This article discusses the implications of the Diabetes Control and Complications Trial for children and adolescents, the Diabetes Prevention Trial-Type I, and several other recent developments in caring for children with insulin-dependent diabetes mellitus.

Consensus Guidelines for the Management of Insulin-dependent Diabetes Mellitus (IDDM) in Childhood and Adolescence

Consensus Guidelines for the Management of Insulin-dependent Diabetes Mellitus (IDDM) in Childhood and Adolescence

Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM.

Iatrogenic hypoglycemia is the limiting factor in the management of insulin-dependent diabetes mellitus (IDDM). It causes recurrent physical morbidity, some mortality, and recurrent or even persistent psychosocial morbidity. The principles of glucose counterregulation, the physiological mechanisms that normally very effectively prevent or correct hypoglycemia, are now known. Decrements in insulin, increments in glucagon, and, in the absence of the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors. Iatrogenic hypoglycemia in IDDM is the result of the interplay of absolute or relative therapeutic insulin excess and compromised glucose counterregulation. Syndromes of compromised glucose counterregulation include defective glucose counterregulation (the result of combined deficiencies of the glucagon and epinephrine responses to falling glucose levels), hypoglycemia unawareness (loss of the warning, neurogenic symptoms of developing hypoglycemia), and elevated glycemic thresholds (lower glucose levels required) for autonomic activation and symptoms during effective intensive therapy. These have been conceptualized as examples of hypoglycemia-associated autonomic failure, a functional disorder distinct from classical diabetic autonomic neuropathy, in IDDM. Recent antecedent iatrogenic hypoglycemia appears to be a major factor in the pathogenesis of hypoglycemia unawareness; there is increasing evidence that this syndrome is reversible with scrupulous avoidance of hypoglycemia. It probably also contributes substantially to the syndrome of elevated glycemic thresholds during intensive therapy. However, factors in addition to recent antecedent hypoglycemia play an important role in the pathogenesis of the syndrome of defective glucose counterregulation. Pending the prevention and cure of IDDM, we need to learn to replace insulin in a much more physiological fashion and/or to prevent, correct, or compensate for compromised glucose counterregulation if we are to eliminate hypoglycemia from the lives of people with IDDM without compromising glycemic control. In the meantime, we must continue to seek better insight into the fundamental mechanisms of compromised glucose counterregulation and to develop practical preventive clinical strategies and practice hypoglycemia risk factor reduction with our patients.