Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

Potential approaches to prevent hypoglycemia-associated autonomic failure.

Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to 'hypoglycemia-associated autonomic failure' (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(KATP) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.

Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans.

Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 µg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ∼30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF's development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.

Preparedness of the CTSA's structural and scientific assets to support the mission of the National Center for Advancing Translational Sciences (NCATS).

The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic science discoveries to clinical practice, ultimately improving the health of the nation. The Clinical and Translational Science Award (CTSA) sites, now housed with NCATS, are organized and prepared to support in this endeavor. The CTSAs provide a foundation for capitalizing on such promise through provision of a disease-agnostic infrastructure devoted to clinical and translational (C&T) science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support.

Opioid receptor blockade prevents exercise-associated autonomic failure in humans.

Hypoglycemia and exercise both induce the release of ß-endorphin, which plays an important role in the modulation of the autonomic response during subsequent events. Because opioid receptor (OR) blockade during antecedent hypoglycemia has been shown to prevent hypoglycemia-associated autonomic failure, we hypothesized that OR blockade during exercise would prevent exercise-associated autonomic failure (EAAF). We studied 8 healthy subjects on 2 consecutive days, each of whom participated in three different studies in random order. The protocol on day 1 involved one of the following: 1) two 90-min hyperinsulinemic-euglycemic clamps plus naloxone infusion (control); 2) two 90-min hyperinsulinemic-euglycemic clamps with exercise at 60% Vo(2max), plus naloxone infusion (N+); or 3) same protocol as in the N+ group, but with saline infusion only (N-). On day 2, all were studied with stepped hyperinsulinemic-hypoglycemic clamps, using hormone concentrations and glucose turnover as indicators of hypoglycemia counterregulation. Compared with control, N- studies resulted in significantly blunted epinephrine and norepinephrine responses to subsequent hypoglycemia. Conversely, the N+ group exhibited unimpaired hypoglycemia counterregulation, characterized by appropriate increases in epinephrine, norepinephrine, and endogenous glucose production. Thus, OR blockade with naloxone during antecedent exercise prevents the development of acute EAAF by improving the catecholamine responses and by restoring endogenous glucose production.

Magnitude of exercise-induced ß-endorphin response is associated with subsequent development of altered hypoglycemia counterregulation.

CONTEXT: ß-Endorphin release in response to recurrent hypoglycemia is implicated in the pathogenesis of hypoglycemia-associated autonomic failure. OBJECTIVE: We hypothesized that exercise-induced ß-endorphin release will also result in the deterioration of subsequent hypoglycemia counterregulation and that the counterregulatory response will negatively correlate with the degree of antecedent ß-endorphin elevation. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Sixteen healthy subjects (six females, aged 26 ± 4.3 yr, body mass index 26.1 ± 5.6 kg/m(2)) were studied with three experimental paradigms on 2 consecutive days. Day 1 consisted of one of the following: 1) two 90-min hyperinsulinemic hypoglycemic clamps (3.3 mmol/liter); 2) two 90-min hyperinsulinemic euglycemic clamps while subjects exercised at 60% maximal oxygen uptake; or 3) two 90-min hyperinsulinemic euglycemic clamps (control). Day 2 followed with hyperinsulinemic (396 ± 7 pmol/liter) stepped hypoglycemic clamps (5.0, 4.4, 3.9, and 3.3 mmol/liter plasma glucose steps). MAIN OUTCOME MEASURES: Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover ([3-(3)H]-glucose) as indicators of recovery from hypoglycemia. RESULTS: There was a significant inverse correlation between plasma ß-endorphin levels during exercise and catecholamine release during subsequent hypoglycemia. Subjects with an exercise-induced rise in ß-endorphin levels to above 25 pg/ml (n = 7) exhibited markedly reduced levels of plasma epinephrine and norepinephrine compared with control (2495 ± 306 vs. 4810 ± 617 pmol/liter and 1.9 ± 0.3 vs. 2.9 ± 0.4 nmol/liter, respectively, P < 0.01 for both). The rate of endogenous glucose production recovery in this group was also much lower than in controls (42 vs. 89%, P < 0.01). CONCLUSIONS: The physiological increase in ß-endorphin levels during exercise is associated with the attenuation of counterregulation during subsequent hypoglycemia.

Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus.

CONTEXT: Recurrent hypoglycemia induces hypoglycemia-associated autonomic failure (HAAF), characterized by deterioration in counterregulatory responses. Endogenous opioids may mediate the development of HAAF, and blockade of opioid receptors with naloxone prevented HAAF in nondiabetic subjects. OBJECTIVE: We hypothesized that opioid receptor blockade with naloxone during antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM) would prevent the development of HAAF. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Eight subjects with T1DM (three women, aged 34 ± 7.4 yr, hemoglobin A1c 7.3 ± 1.1%) were studied on 2 consecutive days on three separate occasions. Day 1 consisted of: 1) two 90-min hypoglycemic clamps (60 mg/dl, N-); 2) two 90-min hypoglycemic clamps (60 mg/dl) with concomitant naloxone infusion (N+); or 3) two 90-min euglycemic clamps (90 mg/dl) with concomitant naloxone infusion (control). Day 2 consisted of hyperinsulinemic stepped hypoglycemic clamps (90, 80, 70, and 60 mg/dl plasma glucose steps). MAIN OUTCOME MEASURES: Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover [(3-(3)H)-glucose] as indicators of recovery from hypoglycemia. RESULTS: Antecedent hypoglycemia in N- group resulted in a markedly decreased epinephrine response and a lower rate of endogenous glucose production (EGP) during subsequent hypoglycemia compared with control (75 ± 17 vs. 187 ± 21 pg/ml, P < 0.05 and 0.8 ± 0.1 vs. 1.4 ± 0.2 mg/kg · min, P < 0.05, respectively). In contrast, in the N+ studies, plasma epinephrine was 164 ± 18 pg/ml and EGP was 1.3 ± 0.2 mg/kg · min during subsequent hypoglycemia, both levels similar to those seen in control studies (P = NS vs. control). Plasma glucagon did not increase with hypoglycemia. CONCLUSIONS: Blockade of endogenous opioids with naloxone during antecedent hypoglycemia improves HAAF in patients with T1DM by ameliorating the epinephrine response and restoring EGP.

Developing a multidisciplinary model of comparative effectiveness research within a clinical and translational science award.

The Clinical and Translational Science Awards (CTSAs) were initiated to improve the conduct and impact of the National Institutes of Health's research portfolio, transforming training programs and research infrastructure at academic institutions and creating a nationwide consortium. They provide a model for translating research across disciplines and offer an efficient and powerful platform for comparative effectiveness research (CER), an effort that has long struggled but enjoys renewed hope under health care reform. CTSAs include study design and methods expertise, informatics, and regulatory support; programs in education, training, and career development in domains central to CER; and programs in community engagement.Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center have entered a formal partnership that places their CTSA at a critical intersection for clinical and translational research. Their CTSA leaders were asked to develop a strategy for enhancing CER activities, and in 2010 they developed a model that encompasses four broadly defined "compartments" of research strength that must be coordinated for this enterprise to succeed: evaluation and health services research, biobehavioral research and prevention, efficacy studies and clinical trials, and social science and implementation research.This article provides historical context for CER, elucidates Einstein-Montefiore's CER model and strategic planning efforts, and illustrates how a CTSA can provide vision, leadership, coordination, and services to support an academic health center's collaborative efforts to develop a robust CER portfolio and thus contribute to the national effort to improve health and health care.

Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade.

CONTEXT: Repeated hypoglycemia is associated with hypoglycemia-associated autonomic failure (HAAF), a syndrome of defective counterregulation. OBJECTIVE: HAAF increases the risk of severe hypoglycemia in diabetes, although its mechanism remains unresolved. Because beta-endorphin influences the autonomic response to hypoglycemia via opioid receptor activation, we hypothesized that it is also involved in the pathogenesis of HAAF. RESEARCH DESIGN AND METHODS: We asked whether opioid receptor blockade during antecedent hypoglycemia (60 mg/dl) on d 1 would prevent development of HAAF on d 2 in eight nondiabetic subjects (five males, 3 females; age, 28 +/- 3.5 yr; body mass index, 24.2 +/- 2.1 kg/m(2)). On four occasions, d 1 was: 1) two 90-min hypoglycemic clamps (N-); 2) two 90-min hypoglycemic clamps plus naloxone (N+); 3) two euglycemic 90-min clamps (C); or 4) two euglycemic 90-min clamps plus naloxone (C+). RESULTS: Day 1 hypoglycemia caused marked deterioration of d 2 hormonal responses to hypoglycemia, consistent with HAAF-i.e. decreased plasma epinephrine, norepinephrine, and glucagon compared to control (C) (374 +/- 71 vs. 810 +/- 94, 307 +/- 65 vs. 686 +/- 98, and 71 +/- 9 vs. 93 +/- 4 pg/ml, respectively, P < 0.01), as well as in endogenous glucose production (24 vs. 163%; P < 0.01). In contrast, naloxone on d 1 completely prevented the defective counterregulatory responses; epinephrine, norepinephrine, and glucagon (852 +/- 82, 769 +/- 77, and 98 +/- 7 pg/ml) and endogenous glucose production recovery (167%) were identical to those after d 1 euglycemia (P < NS for all). Infusion of naloxone alone during euglycemia on d 1 (C+) had no effect on d 2 responses. CONCLUSIONS: These data suggest that the opioid signaling system is a promising target for further studies to prevent HAAF.

Post-challenge hyperglycemia in older adults is associated with increased cardiovascular risk profile.

CONTEXT: Post-challenge hyperglycemia (PCH) is common in older adults and is associated with increased cardiovascular disease (CVD) risk and total mortality. However, PCH is rarely recognized in clinical settings, and the glycemic exposure and CVD risk profile of elderly individuals with PCH has not been defined. OBJECTIVE: The aim of the study was to characterize metabolic and CVD risk profile of elderly subjects with PCH and to determine the effect of acute postprandial metabolic changes on vascular biomarkers. DESIGN: We conducted a cross-sectional study with a standard meal challenge protocol. PARTICIPANTS: Older adults with normal glucose tolerance (n = 30) or PCH (fasting glucose <126 mg/dl and 2-h glucose >or=170 mg/dl; n = 28) participated in the study. MAIN OUTCOME MEASURES: We assessed fasting and postprandial levels of glucose, insulin, lipids, high sensitivity C-reactive protein, plasminogen activator inhibitor-1, and adiponectin and endothelial function using reactive hyperemia peripheral arterial tonometry. RESULTS: Normal glucose tolerance and PCH subjects were matched for age, sex, body mass index, and ethnicity. Fasting glucose (102 +/- 3 vs. 93 +/- 2 mg/dl; P < 0.001) and glycosylated hemoglobin (5.7 vs. 5.4%; P = 0.01) were modestly higher in the PCH group, which was also more insulin resistant (homeostasis model assessment for insulin resistance, 7.0 +/- 1.3 vs. 4.1 +/- 0.6; P = 0.03). Fasting high sensitivity C-reactive protein was higher (2.6 +/- 0.5 vs. 1.3 +/- 0.2 mg/dl; P = 0.05), and adiponectin was lower (11.6 +/- 1.6 vs. 14.0 +/- 1.3 microg/ml; P = 0.03) in subjects with PCH. Peak and 6-h postprandial area under the curve glucose, insulin, and lipids were higher in PCH subjects, who also had higher fasting and postprandial levels of plasminogen activator inhibitor-1. Reactive hyperemia peripheral arterial tonometry declined postprandially only in PCH. CONCLUSIONS: Older adults with PCH experience significant fasting and postprandial metabolic dysregulation, which is accompanied by a proatherosclerotic and prothrombotic vascular profile.

Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone.

CONTEXT: The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes. OBJECTIVE: We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo). PATIENTS: This study included 3548 Diabetes Prevention Program participants. DESIGN: We performed Cox regression analysis using genotype at PPARG P12A, intervention, and their interactions as predictors of diabetes incidence. We also genotyped five other PPARG variants implicated in the response to troglitazone and assessed their effect on insulin sensitivity at 1 yr. RESULTS: Consistent with prior cross-sectional studies, P/P homozygotes at PPARG P12A appeared more likely to develop diabetes than alanine carriers (hazard ratio, 1.24; 95% confidence interval, 0.99-1.57; P=0.07) with no interaction of genotype with intervention. There was a significant interaction of genotype with body mass index and waist circumference (P=0.03 and 0.002, respectively) with the alanine allele conferring less protection in more obese individuals. Neither PPARG P12A nor five other variants significantly affected the impact of troglitazone on insulin sensitivity in 340 participants at 1 yr. CONCLUSIONS: The proline allele at PPARG P12A increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by body mass index. In addition, PPARG P12A has little or no effect on the beneficial response to troglitazone.

Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes.

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulin-induced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA1c 6.5 +/- 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 +/- 4 mg/dl) or hypoglycemia (plasma glucose 58 +/- 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 +/- 38 vs. 2,785 +/- 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 +/- 0.2 vs. 2.5 +/- 0.3 nmol/l, and glucagon 38 +/- 7 vs. 92 +/- 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 +/- 0.14 mg x kg(-1) x min(-1) during euglycemia yet approximately 50% higher with hypoglycemia [1.30 +/- 0.20 mg x kg(-1) x min(-1)], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 +/- 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 +/- 14 to 234 +/- 10 mmol/l (P < 0.001) and accounted for approximately 100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 +/- 23 mmol/l) was significantly lower than in nondiabetic subjects (316 +/- 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 +/- 22 vs. 448 +/- 16 pmol/l in hypoglycemia and 0.9 +/- 0.3 vs. 1.6 +/- 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 +/- 0.5 vs. 1.2 +/- 0.3 mg x kg(-1) x min(-1) compared with euglycemia, P = NS), and hepatic glycogen concentration did not change significantly with hypoglycemia. We conclude that glycogenolysis accounts for the majority of EGP during the first 90 min of hypoglycemia in nondiabetic subjects. In intensively treated type 1 diabetes, despite some activation of counterregulation, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of EGP, factors that may contribute to the defective counterregulation seen in such patients.

Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin.

Insulin resistance and beta-cell dysfunction, two factors central to the pathogenesis of type 2 diabetes, were studied in relation to the development of diabetes in a group of participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP) at baseline and after specific interventions designed to prevent diabetes. Participants were randomly assigned to placebo (n = 1,082), metformin (850 mg twice a day) (n = 1,073), or intensive lifestyle intervention (n = 1,079). The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio = 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity) and with baseline insulin secretion (hazard rate ratio = 0.57-0.76 per SD). Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio = 0.46-0.95 per SD increase and 0.29-0.79 per SD increase, respectively). In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables. The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of beta-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and beta-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and beta-cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups. In conclusion, higher insulin secretion and sensitivity at baseline and improvements in response to treatment were associated with lower diabetes risk in the DPP. The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of beta-cell function.

Fructose normalizes specific counterregulatory responses to hypoglycemia in patients with type 1 diabetes.

We have previously reported that specific counterregulatory responses to hypoglycemia were augmented by an infusion of fructose in nondiabetic humans. We hypothesized that this effect was due to the interaction of a "catalytic" dose of fructose with the regulatory protein for glucokinase in glucose-sensing cells that drive counterregulation. To examine whether fructose could restore counterregulatory responses in type 1 diabetic patients with defective counterregulation, we performed stepped hypoglycemic clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/l glucose steps, 50 min each) in eight intensively treated patients (HbA(1c) 6.4 +/- 0.7%) on two separate occasions: without (control) or with coinfusion of fructose (1.2 mg . kg(-1) . min(-1)). Fructose induced a resetting of the glycemic threshold for secretion of epinephrine to higher plasma glucose concentrations (from 3.3 +/- 0.1 to 3.9 +/- 0.1 mmol/l; P = 0.001) and markedly augmented the increment in epinephrine (by 56%; P < 0.001). The amplification of epinephrine responses was specific; plasma norepinephrine, glucagon, growth hormone, and cortisol were unaffected. Hypoglycemia-induced endogenous glucose production ([3-(3)H]-glucose) rose by 90% (P < 0.001) in the fructose studies, compared with -2.0% (NS) in control. In concert, the glucose infusion rates during the 3.9- and 3.3-mmol/l steps were significantly lower with fructose (2.3 +/- 0.6 and 0.0 +/- 0.0 vs. 5.9 +/- 1.15 and 3.9 +/- 1.0 micromol . kg(-1) . min(-1), respectively; P < 0.001 for both), indicating the more potent counterregulatory response during fructose infusion. We conclude that infusion of fructose nearly normalizes the epinephrine and endogenous glucose production responses to hypoglycemia in type 1 diabetic patients with impaired counterregulation, suggesting that defects in these responses may be dependent on glucokinase-mediated glucose sensing.

Human cerebral blood flow and metabolism in acute insulin-induced hypoglycemia.

How the human brain functions under conditions of acute hypoglycemia remains a complex question by virtue of the potential simultaneous shifts in processes of perfusion, metabolism, and changing demand. We examined this issue by measuring cerebral blood flow (CBF) and oxidative metabolism (CMRO2) in insulin-induced hypoglycemic (HG) and euglycemic (EG) conditions at rest and during motor activation in normal human subjects using magnetic resonance (MR). Experiments were performed on 12 subjects (9M, 3F). The protocol consisted of insulin-induced hypoglycemia (targeting a HG of 60 mg/dL) followed by euglycemia, or in reverse order, each phase lasting approximately 1.5 h. Euglycemia was performed with the same insulin infusion rate so as to match the hypoglycemic phase. Magnetic resonance data were acquired 30 mins after the target plasma glucose was achieved so as to minimize any acute effects. Although the depth of hypoglycemia achieved in the present study was relatively small, the present data found a significant increase in flow in motor cortex with mild hypoglycemia, from 56.4+/-13.6 mL/100 g min (euglycemia) to 64.3+/-7.6 mL/100 g min (hypoglycemia). Using the Renkin-Crone exponential model of oxygen extraction with MR models of susceptibility-based relaxation, analysis of the flow measurements, relaxation and BOLD data also implied that throughout the studies, metabolism and flow remained coupled. Elementary motor task activation was not associated with any consistent larger activated flows. Thus it remains that although mild hypoglycemia induced an increase in basal flow and metabolism, a similar increase was not seen in task activation.

Hypoglycemia in diabetes: common, often unrecognized.

Hypoglycemic episodes in patients with diabetes often go unrecognized, and over time, patients may lose the ability to sense hypoglycemia, increasing their risk. Intensive diabetes control is beneficial for patients with diabetes, but it increases their risk of hypoglycemia, underscoring the complexity of diabetes management.

Lack of effect of sucralose on glucose homeostasis in subjects with type 2 diabetes.

OBJECTIVE: To investigate the effect of 3-months' daily administration of high doses of sucralose, a non-nutritive sweetener, on glycemic control in subjects with type 2 diabetes. DESIGN: A multicenter, double-blind, placebo-controlled, randomized study, consisting of a 6-week screening phase, a 13-week test phase, and a 4-week follow-up phase. SUBJECTS/SETTING: Subjects with type 2 diabetes (age range 31 to 70 years) entered the test phase of this study; 128 subjects completed the study. The subjects were recruited from 5 medical centers across the United States and were, on average, obese. INTERVENTION: Subjects were randomly assigned to receive either placebo (cellulose) capsules (n=69) or 667 mg encapsulated sucralose (n=67) daily for the 13-week test phase. All subjects blindly received placebo capsules during the last 4 weeks of the screening phase and for the entire 4-week follow-up phase. MAIN OUTCOME MEASURES: Glycated hemoglobin (HbA1c), fasting plasma glucose, and fasting serum C-peptide were measured approximately every 2 weeks to evaluate blood glucose homeostasis. Data were analyzed by analysis of variance using repeated measures. RESULTS: There were no significant differences between the sucralose and placebo groups in HbA1c, fasting plasma glucose, or fasting serum C-peptide changes from baseline. There were no clinically meaningful differences between the groups in any safety measure. CONCLUSIONS: This study demonstrated that, similar to cellulose, sucralose consumption for 3 months at doses of 7.5 mg/kg/day, which is approximately three times the estimated maximum intake, had no effect on glucose homeostasis in individuals with type 2 diabetes. Additionally, this study showed that sucralose was as well-tolerated by the study subjects as was the placebo.

Fasting plasma insulin modulates lipid levels and particle sizes in 2- to 3-year-old children.

OBJECTIVE: Obesity and hyperinsulinemia are associated with dyslipidemia in adults and older children, but little is known about these relationships in very young children. We examined the relation of fasting insulin to lipid levels and lipid particle size in young healthy children. RESEARCH METHODS AND PROCEDURES: Analyses were performed on data from 491 healthy 2- and 3-year old Hispanic children enrolled in a dietary study conducted in New York City, 1992-1995. Obesity measures included BMI, ponderal index, skinfold thickness, and waist circumference. Low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol particle size were measured by nuclear magnetic resonance. RESULTS: Fasting insulin level was positively correlated with triglyceride levels (r = 0.24 for boys and r = 0.23 for girls; p < 0.001 for both) and inversely correlated with HDL-cholesterol level in boys (r = -0.20; p < 0.01). Higher fasting insulin level was also correlated with smaller mean HDL particle size in both boys (r = -0.21; p < 0.001) and girls (r = -0.14; p < 0.05) and smaller mean LDL particle size in boys (r = -0.13; p < 0.05). The associations of fasting insulin level with triglyceride and HDL-cholesterol levels and HDL and LDL particle size remained significant after multivariate regression adjustment for age, sex, and BMI or ponderal index. DISCUSSION: Fasting insulin level is associated with relative dyslipidemia in healthy 2- and 3-year-old Hispanic children.