Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes.

Hypoglycaemia is the limiting factor in the glycaemic management of diabetes. Iatrogenic hypoglycaemia is typically the result of the interplay of insulin excess and compromised glucose counterregulation in Type I (insulin-dependent) diabetes mellitus. Insulin concentrations do not decrease and glucagon and epinephrine concentrations do not increase normally as glucose concentrations decrease. The concept of hypoglycaemia-associated autonomic failure (HAAF) in Type I diabetes posits that recent antecedent iatrogenic hypoglycaemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycaemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses). Perhaps the most compelling support for HAAF is the finding that as little as 2 to 3 weeks of scrupulous avoidance of hypoglycaemia reverses hypoglycaemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients. The mediator and mechanism of HAAF are not known but are under active investigation. The glucagon response to hypoglycaemia is also reduced in patients approaching the insulin deficient end of the spectrum of Type II (non-insulin-dependent) diabetes mellitus, and glycaemic thresholds for autonomic (including epinephrine) and symptomatic responses to hypoglycaemia are shifted to lower plasma glucose concentrations after hypoglycaemia in Type II diabetes. Thus, patients with advanced Type II diabetes are also at risk for HAAF. While it is possible to minimise the risk of hypoglycaemia by reducing risks -- including a 2 to 3 week period of scrupulous avoidance of hypoglycaemia in patients with hypoglycaemia unawareness -- methods that provide glucose-regulated insulin replacement or secretion are needed to eliminate hypoglycaemia and maintain euglycaemia over a lifetime of diabetes.

Hypoglycemia-associated autonomic failure in diabetes.

Hypoglycemia is the limiting factor in the glycemic management of diabetes. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to falling glucose levels in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses) and thus a vicious cycle of recurrent hypoglycemia. Perhaps the most compelling support for HAAF is the finding that as little as 2-3 wk of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected individuals. Insight into this pathophysiology has led to a broader view of the clinical risk factors for hypoglycemia to include indexes of compromised glucose counterregulation and provided a framework for the study of the mechanisms of iatrogenic hypoglycemia and, ultimately, its elimination from the lives of people with diabetes.

Hypoglycemia risk reduction in type 1 diabetes.

Hypoglycemia is the limiting factor in the glycemic management of diabetes because it generally precludes maintenance of euglycemia. Improving glycemic control while minimizing hypoglycemia in type 1 diabetes mellitus (T1 DM) involves both application of the principles of aggressive therapy--patient education and empowerment, frequent self monitoring of blood glucose, flexible insulin regimens, individualized glycemic goals and ongoing professional guidance and support--and implementation of hypoglycemia risk reduction. Iatrogenic hypoglycemia is the result of the interplay of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations in T1 DM. Relative or absolute insulin excess occurs when insulin doses are excessive, ill-timed or of the wrong type, when exogenous glucose delivery, endogenous glucose production or insulin clearance are decreased or when insulin-independent glucose utilization or sensitivity to insulin are increased. But these conventional risk factors explain only a minority of episodes of severe hypoglycemia. More potent risk factors include absolute insulin deficiency, a history of severe hypoglycemia and aggressive therapy per se as evidenced by lower glycemic goals, lower hemoglobin A1c levels, or both. These are clinical surrogates of compromised glucose counterregulation, the clinical syndromes of defective glucose counterregulation (the result of absent decrements in insulin and absent increments in glucagon with attenuated increments in epinephrine) and hypoglycemia unawareness (the result of reduced autonomic [sympathochromaffin] activation causing reduced warning symptoms of developing hypoglycemia). The unifying concept of hypoglycemia-associated autonomic failure in T1 DM posits that: (1) Periods of relative or absolute therapeutic insulin excess in the setting of absent glucagon responses lead to episodes of hypoglycemia. (2) These episodes, in turn, cause reduced autonomic (including adrenomedullary) responses to falling glucose concentrations on subsequent occasions. (3) These reduced autonomic responses result in both reduced symptoms of developing hypoglycemia (i.e., hypoglycemia unawareness) and--because epinephrine responses are reduced in the setting of absent glucagon responses--impaired physiological defenses against developing hypoglycemia (i.e., defective glucose counterregulation). Thus a vicious cycle of recurrent hypoglycemia is created and perpetuated. Hypoglycemia risk reduction includes, first, addressing the issue of hypoglycemia--the patient's awareness of and concerns about it, its frequency, severity, timing and clinical settings--in every patient contact. Then it requires application of the principles of aggressive therapy, consideration of both the conventional risk factors and those indicative of compromised glucose counterregulation and appropriate regimen adjustments including a two to three week period of scrupulous avoidance of hypoglycemia in patients with hypoglycemia-associated autonomic failure. With this approach the goals of improving glycemic control and minimizing hypoglycemia are not incompatible.

Blood-to-brain glucose transport, cerebral glucose metabolism, and cerebral blood flow are not increased after hypoglycemia.

Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after approximately 24 h of interprandial hypoglycemia ( approximately 55 mg/dl, approximately 3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P = 0.009), neurogenic symptoms (P = 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain time-activity curves-the latter determined by positron emission tomography (PET)-after intravenous injection of [1-(11)C]glucose at clamped plasma glucose concentrations of 65 mg/dl (3.6 mmol/l). For these calculations, a model was used that includes a fourth rate constant to account for egress of [(11)C] metabolites. Cerebral blood flow was measured with intravenous [(15)O]water using PET. After euglycemia and after hypoglycemia, rates of blood-to-brain glucose transport (24.6 +/- 2.3 and 22.4 +/- 2.4 micromol. 100 g(-1). min(-1), respectively), cerebral glucose metabolism (16.8 +/- 0.9 and 15.9 +/- 0.9 micromol. 100 g(-1). min(-1), respectively) and cerebral blood flow (56.8 +/- 3.9 and 53.3 +/- 4.4 ml. 100 g(-1). min(-1), respectively) were virtually identical. These data do not support the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport during subsequent hypoglycemia. They do not exclude regional increments in blood-to-brain glucose transport. Alternatively, the fundamental alteration might lie beyond the blood-brain barrier.

Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness.

Ultimately traceable to neural glucose deprivation, symptoms of hypoglycemia include neurogenic (autonomic) and neuroglycopenic symptoms. Neurogenic symptoms (tremulousness, palpitations, anxiety, sweating, hunger, paresthesias) are the results of the perception of physiologic changes caused by the autonomic nervous system's response to hypoglycemia. Neuroglycopenic symptoms (confusion, sensation of warmth, weakness or fatigue, severe cognitive failure, seizure, coma) are the results of brain glucose deprivation itself. Glycemic thresholds for symptoms of hypoglycemia shift to lower plasma glucose concentrations following recent episodes of hypoglycemia, leading to the syndrome of hypoglycemia unawareness--loss of the warning symptoms of developing hypoglycemia. Thus, patients with recurrent hypoglycemia (e.g., those with tightly controlled diabetes or with an insulinoma) often tolerate abnormally low plasma glucose concentrations without symptoms.

Hypoglycemia is the limiting factor in the management of diabetes.

Hypoglycemia is the limiting factor, both conceptually and in practice, in the management of diabetes mellitus. While the long-term goal of diabetes research must remain the cure and the prevention of the disease and reasonable near-term goals might include perfect insulin replacement or prevention of complications despite ongoing hyperglycemia, the most pressing short-term goal for people with diabetes would seem to be insight leading to strategies that effectively minimize the risk of hypoglycemia and thus permit low-risk glycemic control. Having reviewed the field in detail recently, the author offers his personal views of the key questions - concerning the physiology of glucose counterregulation, its pathophysiology in diabetes, and hypoglycemia in diabetes - that, if answered, might lead to a reduced risk of iatrogenic hypoglycemia in people with diabetes. The overriding question is: How can we learn to replace insulin more perfectly, prevent, correct or compensate for compromised glucose counterregulation, or both?

Hypoglycemia per se stimulates sympathetic neural as well as adrenomedullary activity, but, unlike the adrenomedullary response, the forearm sympathetic neural response is not reduced after recent hypoglycemia.

We tested the hypotheses that 1) hypoglycemia per se stimulates the sympathetic neural as well as the adrenomedullary component of the sympathochromaffin system, and 2) sympathetic neural responses to hypoglycemia, like adrenomedullary responses, are reduced after recent hypoglycemia. To this end, we studied 10 healthy young adults on 2 consecutive days on two separate occasions, on one occasion with euglycemia (5.0 mmol/l) and on the other occasion with hypoglycemia (2.8 mmol/l) from 1000 to 1200 and 1400 to 1600 on day 1 of each occasion. On day 2 of each occasion, plasma epinephrine and norepinephrine (NE) concentrations and rates of systemic NE spillover (SNESO) and forearm NE spillover (FNESO) were measured during hyperinsulinemic (12.0 pmol x kg(-1) x min(-1)) euglycemia (5.0 mmol/l) and hypoglycemia (2.8 mmol/l). Compared with values during euglycemia, plasma epinephrine and NE and rates of SNESO and FNESO all increased during hypoglycemia (P < 0.01). After day 1 hypoglycemia, there were reductions during hypoglycemia on day 2 in plasma epinephrine (2,050 +/- 500 vs. 2,960 +/- 400 pmol/l; P < 0.02), plasma NE (1.35 +/- 0.16 vs. 1.92 +/- 0.20 nmol/l; P < 0.01), and SNESO rates (5.13 +/- 0.84 vs. 6.87 +/- 0.81 nmol/min; P < 0.02). However, FNESO rates were unaltered (1.16 +/- 0.25 vs. 1.27 +/- 0.17 pmol x min(-1) x 100 ml tissue(-1). Thus we conclude that 1) hypoglycemia per se stimulates both the sympathetic neural and adrenomedullary components of the sympathochromaffin system and 2) adrenomedullary, but not forearm sympathetic neural, responses to hypoglycemia are reduced after recent hypoglycemia. The extent to which the lower plasma NE levels and reduced SNESO responses to hypoglycemia after day 1 hypoglycemia reflect reduced NE release from the adrenal medullae, sympathetic nerves other than those in the forearm, or both cannot be determined from these data.

Insulin resistance in HIV protease inhibitor-associated diabetes.

BACKGROUND: Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy. OBJECTIVE: To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes. DESIGN: Cross-sectional evaluation. PATIENTS: 8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir. MEASUREMENTS: Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell function in vitro. RESULTS: In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat beta-cells. CONCLUSIONS: The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery.

Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease.

BACKGROUND: Although it is now well established that psychiatric depression is associated with adverse outcomes in patients with coronary heart disease (CHD), the mechanism underlying this association is unclear. Elevated heart rate (HR) and plasma norepinephrine (NE), possibly reflecting altered autonomic nervous system activity, have been documented in medically well depressed psychiatric patients, and this pattern is associated with increased risk for cardiac events in patients with CHD. The purpose of this study was to determine whether autonomic nervous system activity is altered in depressed CHD patients. METHODS: HR, plasma NE, and blood pressure (BP) were measured in 50 depressed and 39 medically comparable nondepressed CHD patients at rest and during orthostatic challenge. RESULTS: Resting HR (p = .005), and the change from resting HR at 2, 5, and 10 min after standing (p = .02, .004, and .02, respectively), were significantly higher in the depressed than in the nondepressed patients. There were no differences between the groups in NE or in BP at rest, or in standing minus resting change scores at any time during orthostatic challenge (p < .05). CONCLUSIONS: Depression is associated with altered autonomic activity in patients with CHD, as reflected by elevated resting HR and an exaggerated HR response to orthostatic challenge. Previously reported differences in NE levels between depressed and nondepressed patients were not replicated.

Norepinephrine response to exercise at the same relative intensity before and after endurance exercise training.

It is well documented that endurance exercise training results in a blunted norepinephrine (NE) response to exercise of a given absolute exercise intensity. However, it is not clear what effect training has on the catecholamine response to exercise of the same relative intensity because previous studies have provided conflicting results. The purpose of the present study was, therefore, to determine the catecholamine response to exercise of the same relative exercise intensity before and after endurance exercise training. Six women and three men [age 28 +/- 8 (SD) yr] performed 10 wk of training. Maximal O2 uptake (VO2 max) was determined during treadmill exercise. Fifteen-minute treadmill exercise bouts were performed at 60, 65, 70, 75, 80, and 85% of VO2 max before and after training. VO2 max was increased by 20% (from 39.2 +/- 7.7 to 46.9 +/- 8.1 ml. kg-1. min-1; P < 0.05) in response to training. Plasma NE concentrations were higher (P < 0.05) during exercise at the same relative intensity after, compared with before, training at 65-85% of VO2 max. Differences between heart rates and plasma epinephrine concentrations after, compared with before, training were not statistically significant. These results provide evidence that the NE response to exercise is dependent on the absolute as well as the relative intensity of the exercise.

Effect of short-term fasting on lipid kinetics in lean and obese women.

We evaluated whole body and regional adipose tissue lipid kinetics and norepinephrine (NE) spillover during brief fasting in six lean [body mass index (BMI) 21 +/- 1 kg/m2] and six upper-body obese (UBO; BMI 36 +/- 1 kg/m2) women. At 14 h of fasting, abdominal adipose tissue glycerol and free fatty acid (FFA) release rates were lower (P = 0.07), but whole body glycerol and FFA rates of appearance (Ra) were greater (P < 0.05) in obese than in lean subjects. At 22 h of fasting, glycerol and FFA Ra increased less in obese (19.8 +/- 7.0 and 87.1 +/- 30.3 micromol/min, respectively) than in lean (44.2 +/- 6.6 and 137.4 +/- 30.4 micromol/min, respectively; P < 0.05) women. The percent increase in glycerol Ra correlated closely with the percent decline in plasma insulin in both groups (r2 = 0.85; P < 0.05). Whole body NE spillover declined in lean (P < 0.05) but not obese subjects with continued fasting, whereas regional adipose tissue NE spillover did not change in either group. We conclude that, compared with lean women, in UBO women 1) basal adipose tissue lipolysis is lower, but whole body lipid kinetics is higher because of their greater fat mass; 2) the increase in lipolysis during fasting is blunted because of an attenuated decline in circulating insulin; and 3) downregulation of whole body sympathetic nervous system activity is impaired during fasting.

Impact of nocturnal hypoglycemia on hypoglycemic cognitive dysfunction in type 1 diabetes.

To test the hypothesis that glycemic thresholds for cognitive dysfunction during hypoglycemia, like those for autonomic and symptomatic responses, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM), 15 patients were studied on two occasions. Cognitive functions were assessed during morning hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) after, in random sequence, nocturnal (2330-0300) hypoglycemia (48 +/- 2 mg/dl) on one occasion and nocturnal euglycemia (109 +/- 1 mg/dl) on the other. Compared with nondiabetic control subjects (n = 12), patients with T1DM had absent glucagon (P = 0.0009) and reduced epinephrine (P = 0.0010), norepinephrine (P = 0.0001), and neurogenic symptom (P = 0.0480) responses to hypoglycemia; the epinephrine (P = 0.0460) and neurogenic symptom (P = 0.0480) responses were reduced further after nocturnal hypoglycemia. After nocturnal hypoglycemia, in contrast to nocturnal euglycemia, there was less deterioration of cognitive function overall (P = 0.0065) during hypoglycemia based on analysis of the sum of standardized scores (z-scores). There was relative preservation of measures of pattern recognition and memory (the delayed non-match to sample task, P = 0.0371) and of attention (the Stroop arrow-word task, P = 0.0395), but not of measures of information processing (the paced serial addition task) or declarative memory (the delayed paragraph recall task), after nocturnal hypoglycemia. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, like those for autonomic and symptomatic responses to hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with T1DM.

Managing diabetes: lessons from Type 1 diabetes mellitus.

Glycaemic control is a key component of the successful management of Type 1 and Type 2 diabetes mellitus. Hypoglycaemia is the limiting factor in the management of diabetes because current glucose-lowering regimens are imperfect, defences against decreasing glucose levels in Type 1 and probably Type 2 diabetes are compromised, and low glucose levels have a devastating effect on the brain. Usually, hypoglycaemia precludes the maintenance of normal glucose levels. However, attempts to circumvent the barrier of hypoglycaemia safely are worthwhile because shifting glucose levels towards the non-diabetic range reduces the long-term complications of diabetes. Patient education and empowerment, appropriate self-monitoring of blood glucose, flexible drug regimens, individualized and prudent glycaemic goals, and ongoing professional support are fundamental. Iatrogenic hypoglycaemia is the result of the interplay between excess insulin and compromised glucose counter-regulation in Type 1 and probably Type 2 diabetes. Conventional and newly recognized risk factors must be addressed. Relative or absolute excess insulin occurs when: insulin (or insulin secretagogue) doses are excessive, ill-timed or of the wrong type; the influx of exogenous glucose, endogenous glucose production or insulin clearance are decreased; and insulin-independent glucose utilization or insulin sensitivity are increased. The drug regimen, food ingestion, exercise and alcohol use are under the direct control of the patient and the healthcare provider, and regimen adjustments can be used to address insulin sensitivity and clearance. Unfortunately, these conventional risk factors explain only a minority of episodes of severe hypoglycaemia and therefore the issue of compromised glucose counter-regulation must also be addressed. It is imperative to investigate the patient history for hypoglycaemia unawareness because short-term (e.g. 2 weeks) scrupulous avoidance of hypoglycaemia can restore awareness and improve defective glucose counter-regulation. Until methods of perfect insulin replacement or release are developed, improved regimens and pharmacological methods to minimize hypoglycaemia particularly during the night can be used safely to improve overall glycaemic control.

Reduced epinephrine clearance and glycemic sensitivity to epinephrine in older individuals.

To test the hypothesis that glycemic sensitivity to epinephrine is reduced in older individuals and to assess the impact of a sedentary lifestyle on responses to the hormone, we performed 30-min sequential intravenous infusions of epinephrine (0, 41, 82, 164, 246, and 328 pmol. kg-1. min-1) in young (n = 10) and older (n = 23) healthy subjects. We performed these again after 12 mo of physical training, which raised peak O2 consumption from 24.4 +/- 1.0 to 30.4 +/- 1.4 ml. kg-1. min-1 (P < 0.01) in most of the older subjects (n = 21). During epinephrine infusions, plasma epinephrine concentrations were higher (P = 0.0001) in older than in young subjects (e.g., final values of 7,280 +/- 500 vs. 4,560 +/- 380 pmol/l, respectively), indicating that the clearance of epinephrine from the circulation was reduced in the older individuals. Plasma epinephrine concentration-response curves disclosed reduced glycemic sensitivity to the hormone in the older subjects (P = 0.0001), a finding plausibly attributed to increased sympathetic neural activity, as evidenced here by higher plasma norepinephrine concentrations (P = 0.0001) in the older subjects and consequent desensitization of cellular responsiveness to catecholamines. Training did not correct reduced epinephrine clearance, reduced glycemic sensitivity to epinephrine, or raised norepinephrine levels. We conclude that aging is associated with reduced clearance of epinephrine from the circulation and reduced glycemic sensitivity to epinephrine, the latter plausibly attributed to an age-associated increase in sympathetic neural norepinephrine release. These age-associated changes are not the result of a sedentary lifestyle.