Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle.

Three hypoglycemia-associated clinical syndromes in people with insulin-dependent diabetes mellitus (IDDM)--defective glucose counterregulation, hypoglycemia unawareness, and elevated glycemic thresholds for symptoms and activation of counterregulatory systems during effective intensive therapy--have much in common. They segregate together, are associated with increased frequency of severe iatrogenic hypoglycemia, and share several pathophysiological features, including reduced autonomic nervous system responses to a given degree of hypoglycemia. In the setting of reduced glucagon responses, the reduced adrenomedullary epinephrine responses play a key role in the pathogenesis of iatrogenic hypoglycemia in affected patients. Thus, these syndromes are examples of hypoglycemia-associated autonomic failure in IDDM, a disorder distinct from classical diabetic autonomic neuropathy. The pathogenesis of hypoglycemia-associated autonomic failure is not known, need not be the same in all three syndromes, and could be multifactorial even in a given syndrome. The recent finding that short-term antecedent hypoglycemia results in reduced symptomatic and autonomic (including adrenomedullary) responses to subsequent hypoglycemia in nondiabetic humans leads logically to the following hypothesis concerning one potential pathogenetic mechanism: recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure in IDDM, and hypoglycemia-associated autonomic failure, by reducing both symptoms of and defenses against developing hypoglycemia, results in recurrent severe hypoglycemia, thus creating a vicious cycle. If this hypothesis is confirmed, it will suggest strategies to reduce the frequency of iatrogenic hypoglycemia in people with IDDM.     

Hypoglycemia in IDDM

Hypoglycemia causes substantial morbidity and some mortality in insulin-dependent diabetes mellitus (IDDM). It is often the limiting factor in attempts to achieve euglycemia. The prevention or correction of hypoglycemia normally involves both dissipation of insulin and activation of glucose counterregulatory systems. Among the latter, glucagon plays a primary role initially, whereas epinephrine is not critical, although it becomes critical when glucagon is deficient. Growth hormone and cortisol play demonstrable roles in recovery from prolonged hypoglycemia. Glucose autoregulation may be involved in defense against severe hypoglycemia. With respect to pathophysiology, counterregulatory systems are involved in at least five clinical glucoregulatory syndromes. Defective glucose counterregulation is associated with, and best attributed to, combined deficiencies of the glucagon and epinephrine responses to plasma glucose decrements. Almost assuredly in concert with hypoglycemia unawareness, it results in a markedly increased frequency of severe hypoglycemia, at least during intensive therapy of IDDM. Defined as a night to morning increase in plasma glucose concentration, the dawn phenomenon is thought to result from dissipation of insulin plus the effects of nocturnal growth hormone secretion. Despite a sound rationale, the clinical relevance of the Somogyi phenomenon has been recently questioned. The clinical impression of altered glycemic thresholds for symptoms, i.e., patients with poorly controlled IDDM suffer symptoms of hypoglycemia at relatively high plasma glucose levels, whereas those with very well-controlled IDDM often tolerate subnormal glucose levels, has received experimental support. Clearly, hypoglycemia in IDDM is a problem that needs to be solved. Numerous issues need to be addressed through both basic and clinical research.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multifactorial origin of hypoglycemic symptom unawareness in IDDM. Association with defective glucose counterregulation and better glycemic control

To assess potential relationships between unawareness of hypoglycemic symptoms and both defective glucose counterregulation and therapy-associated altered glycemic thresholds, symptoms and hormonal responses to hypoglycemia were quantitated during standardized insulin infusion tests in 41 patients with insulin-dependent diabetes mellitus (IDDM). The glycemic thresholds for both neurogenic and neuroglycopenic symptoms (and those for both epinephrine and pancreatic polypeptide release) were at lower plasma glucose concentrations in both patients with defective (n = 9, 22%) and those with adequate glucose counterregulation and, among the latter, in patients with lower compared with higher glycosylated hemoglobin levels. The data are consistent with the concept that both defective glucose counterregulation and improved glycemic control contribute to excessive hypoglycemia in IDDM by reducing awareness of symptoms of developing hypoglycemia and by impairing physiological defenses against hypoglycemia. Thus, hypoglycemic symptom unawareness is multifactorial in origin and may be partly reversible.     

Why intraperitoneal delivery of insulin with implantable pumps in NIDDM?

In the normal state, pancreatic secretion of insulin results in a portal/peripheral gradient with the highest concentrations of insulin in the liver. In diabetic patients with absent or insufficient pancreatic insulin secretion who require exogenous insulin, this normal gradient is lost, resulting in numerous abnormalities. This consideration led to interest in the intraperitoneal delivery of insulin, hoping to produce a therapeutic state more closely resembling normal physiology. The development of implantable insulin pumps, which can deliver insulin intraperitoneally, led to numerous studies on insulin-dependent diabetes mellitus (IDDM) patients, demonstrating that insulin delivered intraperitoneally is rapidly and predictably absorbed with most of it going into the portal system, resulting in hepatic delivery of insulin. Studies in IDDM patients have demonstrated that good glucose control can be achieved with intraperitoneal delivery of insulin from implantable pumps with lesser glycemic fluctuations and, therefore, fewer episodes of hypoglycemia. Furthermore, intraperitoneal insulin results in carbohydrate and particularly lipid metabolism that more closely mimics the normal physiological state than produced by injections of insulin. Thus, implantable insulin pumps are being studied for use in IDDM. Many non-insulin-dependent diabetes mellitus (NIDDM) patients have insufficient pancreatic secretion and require exogenous insulin. Because of alterations in hepatic sensitivity to insulin, increments in insulin delivery to the liver may be even more important in NIDDM than IDDM. Furthermore, insulin resistance, which is an integral part of NIDDM, results in higher physiological levels of insulin, which are required for glucose control, and thus significant peripheral hyperinsulinemia occurs in patients receiving exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion

To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (less than 1 mo); 11 with 2.6 +/- 0.3 (mean +/- SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 +/- 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 X min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80-130 ng/m2 X min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = -0.943; P less than 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.     

Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release

To evaluate the effect of strict glycemic control of insulin-dependent diabetes mellitus (IDDM) on the plasma glucose threshold initiating counterregulatory hormone responses to hypoglycemia, we used the glucose clamp technique to produce a standardized gradual glucose decline from 90 to 40 mg/dl in seven young IDDM patients before and after 2-6 mo of intensified insulin therapy. Before intensive therapy [hemoglobin A1 (HbA1) 9.6 +/- 1.1%], epinephrine responses were triggered at a higher plasma glucose level (67 +/- 4 mg/dl) than in normal control subjects (56 +/- 1 mg/dl, P less than .05), and clinical symptoms of hypoglycemia appeared at glucose levels of 50-60 mg/dl. After intensive therapy (HbA1 7.1 +/- 0.7%), the glucose threshold for epinephrine release consistently declined to values (46 +/- 2 mg/dl) below normal (P less than .01). Furthermore, epinephrine concentrations were markedly reduced at each hypoglycemic level, and a greater hypoglycemic stimulus was required to elicit symptoms. The glucose threshold stimulating release of growth hormone also significantly declined after intensive therapy. We conclude that strict glycemic control of IDDM lowers the plasma glucose level required to generate epinephrine release during hypoglycemia. This may diminish patient recognition of moderate hypoglycemia and increase the risk of severe hypoglycemia in intensively treated IDDM.     

Perioperative management of diabetic patients

Diabetes mellitus is the most common metabolic disease. New classifications have recently been proposed by the American Diabetes Association (ADA) and the World Health Organization (WHO). Type 1 (formerly insulin-dependent diabetes mellitus IDDM) is immune-mediated and leads to absolute insulin deficiency. Type 2 diabetes (formerly non-insulin-dependent diabetes mellitus [NIDDM]) is a disease of adult onset and is associated with insulin resistance. Type 3 corresponds to a wide range of specific types of diabetes, including various genetic defects of beta-cell function and insulin action, diseases of exocrine pancreas, endocrinopathies, and drug-induced diabetes. Type 4 is gestational diabetes (Table 1). Diabetics undergoing surgery have increased mortality, and type 1 diabetics are particularly at risk of postoperative complications. Wound complications are increased in diabetics, and healing is severely impaired when glycemic control is poor. However, with the use of modern management plans, the major outcome measures of surgery are comparable in diabetic and nondiabetic patients. Successful management of surgery in diabetic patients requires simple and safe protocols, which are fully understood by all staff and a close liaison among the surgeons, diabetes care team, and anesthetists. There is no consensus on the optimal metabolic management of the diabetic patient during surgery. Several surveys have highlighted the inconsistency with which surgical problems are managed in diabetic patients. The aim of this article is to provide protocols to achieve sensible and practical glycemic control in diabetic patients undergoing surgery.     

Diabetic end-stage renal failure with autonomic dysfunction and spontaneous hypoglycemia during fasting

Spontaneous hypoglycemia during fasting was frequently observed in a 53-year old man with diabetic end-stage renal failure. On fasting, despite being managed on dietary therapy, this patient developed hypoglycemia (independent of hemodialysis), at which time he was lethargic. He showed severe autonomic dysfunction for a long period. No significant transient increase in catecholamines was not observed in response to the Schellong test or during the hypoglycemic episodes. During the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT), basal insulin level was not detectable, and insulin response was absent. Glucagon loading test and epinephrine loading test suggested that the glycogen store in the liver was maintained, but that glycogenolysis was impaired. Lack of catecholamine response and diminished glucagon response to hypoglycemia because of autonomic disinnervation may suppress hepatic glycogenolysis and renal gluconeogenesis, thereby resulting in fasting hypoglycemia in pathologic situations such as diabetes mellitus and renal insufficiency. Received: August 6, 1999 / Accepted: October 14, 1999     

Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes

Iatrogenic hypoglycemia is a problem for people with diabetes. It causes recurrent morbidity, and sometimes death, as well as a vicious cycle of recurrent hypoglycemia, precluding maintenance of euglycemia over a lifetime of diabetes. Improved therapeutic approaches that will minimize both hypo- and hyperglycemia will be based on insight into the pathophysiology of glucoregulation, specifically glucose counterregulation, in insulin-deficient (type 1 and advanced type 2) diabetes. In such patients, hypoglycemia is the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological (the syndrome of defective glucose counterregulation) and behavioral (the syndrome of hypoglycemia unawareness) defenses against falling plasma glucose concentrations. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses to a given level of subsequent hypoglycemia in the setting of absent decrements in insulin and absent increments in glucagon) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses to a given level of subsequent hypoglycemia) and thus a vicious cycle of recurrent hypoglycemia. The clinical impact of HAAF is well established in type 1 diabetes; it also affects those with advanced type 2 diabetes. It is now known to be largely reversible, by as little as 2-3 weeks of scrupulous avoidance of hypoglycemia, in most affected patients. However, the mechanisms of HAAF and its component syndromes are largely unknown. Loss of the glucagon secretory response, a key feature of defective glucose counterregulation, is plausibly explained by insulin deficiency, specifically loss of the decrement in intraislet insulin that normally signals glucagon secretion as glucose levels fall. Reduced neurogenic symptoms, a key feature of hypoglycemia unawareness, are largely the result of reduced sympathetic neural responses to falling glucose levels. The mechanism by which hypoglycemia shifts the glycemic thresholds for sympathoadrenal activation to lower plasma glucose concentrations, the key feature of both components of HAAF, is not known. It does not appear to be the result of the release of a systemic mediator (e.g., cortisol, epinephrine) during antecedent hypoglycemia or of increased blood-to-brain glucose transport (although increased transport of alternative fuels is conceivable). It is likely the result of alterations of brain metabolism. Although there is an array of clues, the specific alteration remains to be identified. While the research focus has been largely on the hypothalamus, hypoglycemia is now known to activate widespread brain regions, including the medial prefrontal cortex. The possibility that HAAF could be the result of posthypoglycemic brain glycogen supercompensation has also been raised. Finally, there appear to be diverse causes of HAAF. In addition to recent antecedent hypoglycemia, these include exercise- and sleep-related HAAF. Clearly, a unifying mechanism of HAAF would need to incorporate these causes as well. Pending the prevention and cure of diabetes, critical fundamental, translational, and outcomes research is needed if we are to eliminate hypoglycemia from the lives of people affected by diabetes.     

Diabetic muscle infarction after simultaneous pancreas-kidney transplant

Diabetic muscle infarction (DMI) is a rare entity that occurs in patients with long-standing type 1 insulin dependent diabetes mellitus (IDDM). We describe DMI occurring on an average of 5 months after SPK in four patients with IDDM and end stage renal disease (ESRD). These patients had evidence of other long-term diabetic complications including retinopathy and neuropathy, as well as microangiopathy and hypercoagulability, both of which are pre-disposing factors for DMI. The etiology of DMI is not well understood. Despite establishment of normoglycemia after kidney-pancreas transplantation, DMI may occur as a result of tissue damage/fragility secondary to the pre-existing long-term labile glycemic control and hypertension. This may be exacerbated by the pro-coagulant effects of the calcineurin-inhibitors and the use of steroids as part of the immunosuppressive regimen.     

Decreased bronchial response to methacholine in IDDM patients with autonomic neuropathy

This study was designed to evaluate the involvement of airways innervation during diabetic autonomic neuropathy. Bronchial response to methacholine was assessed by inhalation of serially doubling doses in 22 insulin-dependent diabetes mellitus (IDDM) patients and 11 nondiabetic control subjects selected for their nonsmoking habits. Cardiovascular autonomic control was studied by four standardized tests, i.e., blood pressure and heart-rate variations during orthostatism, heart-rate variation during Valsalva maneuver, and deep breathing. Magnitude and time-course of response to methacholine were similar in nondiabetic subjects and IDDM patients without any abnormal result on cardiovascular tests. Conversely, bronchial response to methacholine was markedly reduced in IDDM patients with one or more abnormal results by cardiovascular assessment of autonomic control. In the IDDM patients, bronchial response to methacholine was significantly correlated to indexes of cardiovascular autonomic control. These results suggest that, during diabetic neuropathy, innervation of the airways likewise involves cardiac autonomic control and leads to impairment of defense reflexes of the airways.     

Lilly lecture 1988. Glucose counterregulation and its impact on diabetes mellitus

Glucose counterregulation is the sum of processes that protect against development of hypoglycemia and that restore euglycemia if hypoglycemia should occur. In order of importance, the key counterregulatory factors are glucagon, epinephrine, growth hormone, cortisol, and hepatic autoregulation. These act primarily by increasing hepatic glucose output, initially via breakdown of glycogen and later by gluconeogenesis. In people without diabetes and in people with type II (non-insulin-dependent) diabetes, suppression of endogenous insulin secretion during hypoglycemia is also important in permitting full expression of the effects of counterregulation. People with diabetes are more prone to develop hypoglycemia for various reasons (e.g., insulin overdose, skipped meals, and intensive exercise); one that has recently been identified is impaired glucose counterregulation: patients with type I (insulin-dependent) diabetes (and to a lesser extent, patients with type II diabetes) lose the glucagon response to hypoglycemia; subsequent development of autonomic neuropathy with concomitant loss of the epinephrine response leads to almost complete paralysis of counterregulation and loss of recognition of hypoglycemia. To make matters worse, an episode of hypoglycemia that causes activation of counterregulation can lead to rebound hyperglycemia (Somogyi phenomenon); if this is improperly treated, brittle diabetes may follow. Thus, abnormalities in glucose counterregulation may predispose to severe hypoglycemia and prevent achievement of optimal glycemic control in patients with diabetes.     

Effects of long-term optimization and short-term deterioration of glycemic control on glucose counterregulation in type I diabetes mellitus

To assess the effects of glycemic control on glucose counterregulation, rates of plasma glucose recovery from hypoglycemia and counterregulatory hormonal responses were studied in 18 C-peptide-negative patients with insulin-dependent diabetes mellitus (IDDM) before and after either improvement, no change, or deterioration in glycemic control. Hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 X min for 1 h) after maintenance of euglycemia overnight with i.v. insulin. In 13 patients with long duration of IDDM (9 +/- 0.5 yr, mean +/- SEM) and initially poor glycemic control (mean diurnal blood glucose, MBG 199 +/- 8 mg/dl, ketoamine-HbA1 12.4 +/- 0.2%; nondiabetic subjects 104 +/- 4 mg/dl and 6.8 +/- 0.09%, respectively), rates of plasma glucose recovery from hypoglycemia (0.30 +/- 0.01 versus 0.60 +/- 0.01 mg/dl X min in nondiabetic subjects, P less than 0.001) and plasma glucagon (AUC 0.56 +/- 0.09 versus 6.3 +/- 0.50 ng/ml X 150 min in nondiabetic subjects, P less than 0.01) and epinephrine (AUC 16.9 +/- 0.2 versus 25.7 +/- 0.2 ng/ml X 150 min in nondiabetic subjects, P less than 0.001) responses to hypoglycemia were impaired. Intensive therapy (three daily injections of insulin) instituted in 7 out of 13 IDDM patients for up to 9 mo improved MBG (124 +/- 6 mg/dl, P less than 0.01) and ketoamine-HbA1 (7.9 +/- 0.02%, P less than 0.01) but not rates of plasma glucose recovery (0.31 +/- 0.01 mg/dl X min) and plasma glucagon (AUC 0.69 +/- 0.07 ng/ml X 150 min) and epinephrine (AUC 14.9 +/- 0.17 ng/ml X 150 min) responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic Insulin Gene Therapy in Insulin-Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease resulting in destruction of the pancreatic beta-cells in the islets of Langerhans. Commonly employed treatment of IDDM requires periodic insulin therapy, which is not ideal because of its inability to prevent chronic complications such as nephropathy, neuropathy and retinopathy. Although pancreas or islet transplantation are effective treatments that can reverse metabolic abnormalities and prevent or minimize many of the chronic complications of IDDM, their usefulness is limited as a result of shortage of donor pancreas organs. Gene therapy as a novel field of medicine holds tremendous therapeutic potential for a variety of human diseases including IDDM. This review focuses on the liver-based gene therapy for generation of surrogate pancreatic beta-cells for insulin replacement because of the innate ability of hepatocytes to sense and metabolically respond to changes in glucose levels and their high capacity to synthesize and secrete proteins. Recent advances in the use of gene therapy to prevent or regenerate beta-cells from autoimmune destruction are also discussed.     

Prospective analysis of the insulin-resistance syndrome (syndrome X).

Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including hypertension, dyslipidemia, and non-insulin-dependent diabetes mellitus. This syndrome has been termed Syndrome X. An important limitation of previous studies has been that they all have been cross sectional, and thus the presence of insulin resistance could be a consequence of the underlying metabolic disorders rather than its cause. We examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in the 8-yr follow-up of the cohort enrolled in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. In univariate analyses, fasting insulin was related to the incidence of the following conditions: hypertension, decreased high-density lipoprotein cholesterol concentration, increased triglyceride concentration, and non-insulin-dependent diabetes mellitus. Hyperinsulinemia was not related to increased low-density lipoprotein or total cholesterol concentration. In multivariate analyses, after adjustment for obesity and body fat distribution, fasting insulin continued to be significantly related to the incidence of decreased high-density lipoprotein cholesterol and increased triglyceride concentrations and to the incidence of non-insulin-dependent diabetes mellitus. Baseline insulin concentrations were higher in subjects who subsequently developed multiple metabolic disorders. These results were not attributable to differences in baseline obesity and were similar in Mexican Americans and non-Hispanic whites. These results support the existence of a metabolic syndrome and the relationship of that syndrome to multiple metabolic disorders by showing that elevations of insulin concentration precede the development of numerous metabolic disorders.     

Membrane lipid alterations and Na+-pumping activity in erythrocytes from IDDM and NIDDM subjects

The Na+-pumping activity of the erythrocyte plasma membrane in diabetic subjects was studied together with the lipid composition. Insulin-dependent diabetes mellitus (IDDM) patients (n = 25) were divided into young (28.1 +/- 7.4 yr old, mean +/- SD; n = 16) and old (7.17 +/- 9.8 yr old; n = 10) subjects; the age of non-insulin-dependent (NIDDM) patients was 70.7 +/- 11.5 yr (n = 10). The Na+-pumping activity, estimated from both Na+-K+-ATPase and ouabain binding, was significantly decreased in IDDM and NIDDM subjects, but its insulin sensitivity was retained only in young IDDM subjects. The total cholesterol and phospholipid content of the erythrocyte plasma membrane was lowered in IDDM subjects, and cholesterol-to-phospholipid molar ratio was significantly decreased. In NIDDM subjects the significant decreased of the two lipid components did not alter their ratio. The analysis of major phospholipid components of erythrocyte membranes revealed that only phosphatidylcholine is significantly increased in young diabetic subjects. The fatty acid composition of major phospholipid classes was significantly altered in all cases: the unsaturation index appeared to be increased in phosphatidylserine and sphingomyelin for both IDDM and NIDDM subjects and was also increased in phosphatidylcholine in the latter group.     

Risk of early-onset proliferative retinopathy in IDDM is closely related to cardiovascular autonomic neuropathy.

Determinants of proliferative diabetic retinopathy (PDR) that occur during the 2nd decade of insulin-dependent diabetes mellitus (IDDM) (early-onset PDR) were investigated in a nested case-control study. From an inception cohort of patients with juvenile-onset IDDM that now has 15-21 yr diabetes duration, the patients with PDR (cases, n = 74) were selected for study along with a random sample of the patients in the cohort without PDR (control subjects, n = 88). The risk of PDR was associated with poor glycemic control during the first 12 yr of diabetes. Relative to patients in the first quartile of the index of hyperglycemia, those in higher quartiles and nonattenders had a four- to fivefold risk of developing PDR. A striking relationship with cardiovascular autonomic neuropathy (CAN) was found. Relative to patients without CAN, patients with significant and mild CAN had odds ratios of 77.5 and 34.6, respectively. Patients with albumin excretion rates greater than 30 micrograms/min had moderately increased risk of PDR (ranging from 4-fold for microalbuminuria to 7-fold for proteinuria). In contrast, patients with impaired renal function had an extremely high risk of PDR. All 20 of these patients were cases, therefore the odds ratio was infinite. All three factors (poor glycemic control, CAN, and various stages of nephropathy) were associated with PDR in multiple logistic regression analysis. However, in models including glycemic control, the association between microalbuminuria or proteinuria and PDR was weakened. In conclusion, our findings are consistent with a hypothesis that the level of glycemia is a primary determinant of early-onset PDR.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo relationship between insulin clearance and action in healthy subjects and IDDM patients

The relationship between plasma clearance rate of insulin (PCR) and insulin-stimulated glucose disposal was investigated in 15 healthy subjects and 30 insulin-dependent diabetes mellitus (IDDM) patients with the sequential euglycemic (5 mM) clamp technique (insulin infusion rates of 0.5, 1, 2, and 5 mU.kg-1.min-1 in 2-h steps). In IDDM patients, insulin-stimulated glucose disposal was decreased at low insulinemia (steps 1-3), whereas at maximal insulinemia (step 4), insulin action was normal. In the healthy subjects, strong positive correlations were found for PCR versus steady-state glucose infusion rate (SSGIR): r = 0.71 (P less than 0.005), 0.72 (P less than 0.005), 0.72 (P less than 0.005), and 0.78 (P less than 0.001) for steps 1-4, respectively. In contrast, in the IDDM patients, no relationship was observed: r = 0.01, -0.03, 0.06, and 0.01 (NS) for steps 1-4, respectively. In univariate analyses of PCR, no differences were found between patient subgroups with values for percentage of tracer binding below or above 5% or insulin-antibody-binding capacities and equilibrium constants below or above the median. In multiple regression models, adjusting for insulin antibodies, preceding glycemic control (HbA1 or fructosamine), and duration of IDDM, correlations for PCR versus SSGIR remained nonsignificant. In conclusion, insulin action is correlated to insulin clearance in healthy subjects, suggesting a functional relationship from an in vivo perspective. No such relationship was present in patients with IDDM, even after adjusting for insulin antibodies, preceding glycemic control, and duration of IDDM.     

Antecedent Hypoglycemia Impairs Autonomic Cardiovascular Function: Implications for Rigorous Glycemic Control

OBJECTIVE— Glycemic control decreases the incidence and progression of diabetic complications but increases the incidence of hypoglycemia. Hypoglycemia can impair hormonal and autonomic responses to subsequent hypoglycemia. Intensive glycemic control may increase mortality in individuals with type 2 diabetes at high risk for cardiovascular complications. We tested the hypothesis that prior exposure to hypoglycemia leads to impaired cardiovascular autonomic function.RESEARCH DESIGN AND METHODS— Twenty healthy subjects (age 28 ± 2 years; 10 men) participated in two 3-day inpatient visits, separated by 1–3 months. Autonomic testing was performed on days 1 and 3 to measure sympathetic, parasympathetic, and baroreflex function. A 2-h hyperinsulinemic [hypoglycemic (2.8 mmol/l) or euglycemic (5.0 mmol/l)] clamp was performed in the morning and in the afternoon of day 2.RESULTS— Comparison of the day 3 autonomic measurements demonstrated that antecedent hypoglycemia leads to 1) reduced baroreflex sensitivity (16.7 ± 1.8 vs. 13.8 ± 1.4 ms/mmHg, P = 0.03); 2) decreased muscle sympathetic nerve activity response to transient nitroprusside-induced hypotension (53.3 ± 3.7 vs. 40.1 ± 2.7 bursts/min, P < 0.01); and 3) reduced (P < 0.001) plasma norepinephrine response to lower body negative pressure (3.0 ± 0.3 vs. 2.0 ± 0.2 nmol/l at −40 mmHg).CONCLUSIONS— Baroreflex sensitivity and the sympathetic response to hypotensive stress are attenuated after antecedent hypoglycemia. Because impaired autonomic function, including decreased cardiac vagal baroreflex sensitivity, may contribute directly to mortality in diabetes and cardiovascular disease, our findings raise new concerns regarding the consequences of hypoglycemia.Control of blood glucose is the cornerstone of diabetes management because glycemic control decreases the incidence and progression of diabetic microvascular (1–4) and, in some studies, macrovascular complications (2,5). However, rigorous glycemic control leads to an increased incidence of hypoglycemia (1,6). Even a single episode of hypoglycemia may impair the counterregulatory metabolic and autonomic responses to subsequent hypoglycemia (7). Recently, evidence has emerged suggesting an association between hypoglycemia and increased mortality in critically ill patients receiving insulin therapy (8). An increase in mortality was also observed in the highly intensive treated limb (targeting A1C values of <6%) of a multicenter clinical trial of individuals with type 2 diabetes at high risk for cardiovascular disease events (9). The cause of the mortality in these studies could not be directly attributed to hypoglycemia.Cardiovascular autonomic impairment is associated with and may cause increased mortality (10–14). Autonomic neuropathy is a predictor of increased mortality in many diabetic cohort studies (10,11). In addition, impaired heart rate variability is associated with increased risk of mortality in patients after a myocardial infarct (12). More recent studies in the postmyocardial infarction population have shown that impaired baroreflex sensitivity is an independent predictor of cardiac mortality (13,14).In an effort to extend our understanding of the effect of hypoglycemia on the autonomic nervous system, we tested the hypothesis that prior exposure to hypoglycemia would lead to impaired control of cardiovascular autonomic function. We therefore examined cardiovascular autonomic function using standardized tests measuring sympathetic, parasympathetic, and baroreflex function before and after euglycemic-hyperinsulinemic and hypoglycemic-hyperinsulinemic clamp studies.     

Higher glycemic thresholds for symptoms during beta-adrenergic blockade in IDDM.

We tested the hypotheses that nonselective beta-adrenergic blockade does not cause absolute hypoglycemia unawareness but shifts the glycemic thresholds for symptoms to lower plasma glucose concentrations and that neither neuroglycopenic symptoms nor cognitive impairments during hypoglycemia are altered by beta-adrenergic blockade. To do so, we applied the euglycemic and stepped hypoglycemic clamp techniques to patients with moderately controlled insulin-dependent diabetes mellitus (IDDM) in the absence (n = 8) and presence (n = 9) of the nonselective beta-adrenergic antagonist propranolol. Compared with the corresponding euglycemic clamps, total symptom scores first increased at the 4.4-mM plasma glucose step (a higher level than that of 2.8 mM in nondiabetic subjects studied previously) in the absence of propranolol. Beta-adrenergic blockade did not produce absolute hypoglycemia unawareness. Indeed, at the frankly hypoglycemic step of 2.8 mM, total symptom scores tended to be higher in the presence than in the absence of propranolol. This was largely the result of greater (P less than 0.01) perception of diaphoresis. However, symptom scores did not increase until the 3.3-mM plasma glucose step during beta-adrenergic blockade. The perception of hunger, and perhaps that of tremulousness, was reduced by propranolol at the higher glucose steps. Neuroglycopenic symptoms were not reduced by propranolol. The cognitive function of memory, but not that of attention, was impaired, also starting at the 4.4-mM glucose step. This was not impaired further by propranolol. Thus, we formed the following conclusions. 1) Nonselective beta-adrenergic blockade does not cause absolute hypoglycemia unawareness but shifts the glycemic thresholds for symptoms to lower plasma glucose concentrations in patients with IDDM. 2) Beta-adrenergic blockade does not reduce neuroglycopenic symptoms, and it does not further impair cognitive function during hypoglycemia in IDDM patients.