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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 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.

Repeated hypoglycemic episodes can cause HAAF, i.e., blunted counter-regulatory hormone responses. We have shown that activating opiate receptors can induce HAAF in healthy participants subjected to subsequent experimentally induced hypoglycemia. However, we have noted inter-individual variability in the development of HAAF. In our current study we evaluated the effect of blocking opioid receptors with intranasal naloxone in individuals at risk for HAAF. To identify people susceptible to HAAF, fourteen nondiabetic subjects (13M, age 43.4±8.0, BMI 25.5±2.19 kg/m2) underwent two 120-minute hyperinsulinemic hypoglycemic (nadir 54 mg/dl) clamp studies on Day 1 and a third hypoglycemic clamp study on Day 2. Nine individuals developed HAAF, defined as ≥20% reduction in average epinephrine (EPI) levels (90-120 minutes) between the first and third episodes of hypoglycemia (858 ±161 vs. 494±108 pg/ml, p=0.008). The HAAF-prone subjects underwent similar 3-episode hypoglycemic studies on two subsequent occasions with hourly placebo (randomized, double-blinded) or naloxone (4 mg) on Day 1. While average EPI levels declined from the first to the third hypoglycemic episode by 42% with placebo (p=0.01), levels did not differ with intranasal naloxone (p=0.67). Similarly, plasma glucagon levels decreased significantly from the first to the third hypoglycemic episode with placebo but were maintained with naloxone (Glucagon 1st vs. 3rd episode: Placebo 31.5±8.07 vs. 21.6±5.3 mg/ml, p=0.03; Naloxone 30.5±7.42 vs. 27.0±6.9 mg/ml, p=0.41). Naloxone did not alter plasma cortisol responses or hypoglycemic symptoms. This confirms previous reports of inter-individual variability in development of HAAF. Administration of intranasal naloxone during antecedent hypoglycemia prevented HAAF in susceptible individuals. Inhaled naloxone may offer a feasible approach to ameliorate HAAF in targeted individuals at risk for hypoglycemia-related adverse events. Disclosure A. Manavalan: None. P.M. Mathias: None. S. Aleksic: None. E. Lontchi Yimagou: None. M. Carey: None. J. Moy: None. T. Patel: None. B. Kuo: None. O. Sandu: None. H. Shamoon: None. M. Hawkins: None. Funding National Institutes of Health (R01DK079974)

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.

Recurrent hypoglycemia leads to HAAF, with blunted counterregulatory hormone responses to subsequent hypoglycemic episodes. A recent report suggested inter-individual differences in susceptibility to HAAF (JCEM 102:3571, 2017). Since adrenergic receptor blockade prevents HAAF (Diabetes 60:602, 2011), we investigated to what extent the rises in plasma epinephrine (EPI) associated with hypoglycemia predict the development of HAAF. Healthy non-diabetic subjects (n=18, age 43±2years, BMI 25±1 kg/m2) underwent two 2-hour hypoglycemic clamp studies (nadir 54mg/dl; 0-2h and 4-6 h) on Day 1 followed by a third 2-hour hypoglycemic clamp on Day 2. Twelve subjects (67%) developed HAAF by the third episode, as defined by at least 20% reductions in peak EPI levels (peak EPI 1st vs. 3rd episode: HAAF subjects 1072±156 vs. 530±87pg/ml, p To specifically define the role of EPI in the pathogenesis of HAAF, we challenged an additional seven non-diabetic subjects (age 32±4 years, BMI 25±1 kg/m2) with two 2-hour infusions of EPI (0.03 μg/kg/min;0-2h and 4-6 h) on Day 1 followed by 200-minute stepped hypoglycemic clamps (90, 80, 70 and 60 mg/dl, each for 50 minutes) on Day 2. Compared to saline, EPI infusion on Day 1 induced 40% and 28% reductions in epinephrine response to hypoglycemia at the 70 and 60 mg/dl glucose steps on Day 2, respectively (all p Thus, rises in EPI similar to those seen with hypoglycemia reproduce key features of HAAF in non-diabetic subjects. Marked inter-individual variability in EPI levels in response to hypoglycemia may explain why some people are more prone to develop HAAF. Disclosure E. Lontchi Yimagou: None. S. Aleksic: None. L. Upadhyay: None. S. Sharma: None. M. Carey: None. A. Goyal: None. J. You: None. R. Hulkower: None. S. Murthi: None. W.G. Mitchell: None. H. Shamoon: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc. Funding American Diabetes Association (1-18-PMF-024 to E.L.Y.); National Institutes of Health (R01DK079974)

Attainment of near-normal glycemic goals in type 1 diabetes (T1D) is limited by iatrogenic hypoglycemia. Repeated episodes of hypoglycemia lead to Hypoglycemia-Associated Autonomic Failure (HAAF), with blunted counter-regulatory hormone responses. We previously reported that pharmacologic activation of opioid receptors experimentally recapitulates some features of HAAF (Diabetes 66:2764; 2017), and opioid antagonism with intravenous naloxone prevents experimentally induced HAAF in healthy subjects. We therefore hypothesized that intranasal naloxone would augment central blockade of opioid receptors by bypassing the blood-brain barrier, and would provide a feasible outpatient approach to prevent HAAF. Using a randomized, double-blinded placebo-controlled study design, 7 healthy subjects (7M; age 43±3 year; BMI 25.9±0.9 kg/m2) participated in paired two-day studies, 5 weeks apart. Day 1 consisted of two 120 minute hypoglycemic (∼54 mg/dl) hyperinsulinemic clamps, with hourly intranasal administration of either saline (placebo) or naloxone (4 mg hourly). On day 2, subjects underwent one 120 minute hypoglycemic clamp (∼54 mg/dl). As expected, HAAF was experimentally induced in the placebo studies, based on lower peak epinephrine levels (mean±SEM: first hypoglycemic episode=1375±182 vs. third episode=858±235, pg/ml, p=0.004). With intranasal naloxone, epinephrine levels did not differ from the first to the third hypoglycemic episode (first=942±190 vs. third episode=857±134 pg/ml, p=0.4). Naloxone did not alter the responses of plasma glucagon, cortisol or growth hormone, or hypoglycemic symptoms. These findings suggest that HAAF can be prevented by acute blockade of opioid receptors during hypoglycemia, presumably by inhibiting opioid receptor activation by circulating endorphins. Thus, acute self-administration of intranasal naloxone could be an effective and feasible ’real-world’ approach to ameliorate HAAF in T1D. Disclosure S. Aleksic: None. E. Lontchi-Yimagou: None. R. Hulkower: None. M. Carey: None. M. Ude: None. W.G. Mitchell: None. O. Sandu: None. N. Tomuta: None. H. Shamoon: None. M. Hawkins: None.

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.

Aims To examine the ability of fasting plasma glucose (FPG) and/or 2-h glucose to confirm diabetes and to determine the proportion of participants with HbA1c ≥ 6.5%. Methods Diabetes confirmation rates were calculated after a single elevated FPG and/or 2-h glucose on an oral glucose tolerance test (OGTT) using a confirmatory OGTT performed within 6 weeks. Results 772 (24%) participants had elevated FPG or 2-h glucose on an OGTT that triggered a confirmation visit. There were 101 triggers on FPG alone, 574 on 2-h glucose alone, and 97 on both. Only 47% of participants who triggered had confirmed diabetes. While the confirmation rate for FPG was higher than that for 2-h glucose, the larger number of 2-h glucose triggers resulted in 87% of confirmed cases triggering on 2-h glucose. Confirmation rates increased to 75% among persons with FPG ≥ 126 mg/dl and HbA1c ≥ 6.5%. Conclusions Only half of the persons with elevated FPG and IGT were subsequently confirmed to have diabetes. At current diagnostic levels, more persons trigger on 2-h glucose than on FPG, but fewer of these persons have their diagnoses confirmed. In individuals with FPG ≥ 126 mg/dl and HbA1c ≥ 6.5%, the confirmation rate was increased.

Hypoglycemia and exercise both induce the release of β-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% Vo2max, 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.

β-Endorphin release in response to recurrent hypoglycemia is implicated in the pathogenesis of hypoglycemia-associated autonomic failure.We hypothesized that exercise-induced β-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 β-endorphin elevation.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).Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover ([3-(3)H]-glucose) as indicators of recovery from hypoglycemia.There was a significant inverse correlation between plasma β-endorphin levels during exercise and catecholamine release during subsequent hypoglycemia. Subjects with an exercise-induced rise in β-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, P0.01 for both). The rate of endogenous glucose production recovery in this group was also much lower than in controls (42 vs. 89%, P0.01).The physiological increase in β-endorphin levels during exercise is associated with the attenuation of counterregulation during subsequent hypoglycemia.

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.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.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).Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover [(3-(3)H)-glucose] as indicators of recovery from hypoglycemia.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, P0.05 and 0.8 ± 0.1 vs. 1.4 ± 0.2 mg/kg · min, P0.05, 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.Blockade of endogenous opioids with naloxone during antecedent hypoglycemia improves HAAF in patients with T1DM by ameliorating the epinephrine response and restoring EGP.

The Clinical and Translational Science Awards (CTSAs) were initiated to improve the conduct and impact of NIH'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 robust programs in community engagement, both of the general public and of clinical practice communities.

Insulin resistance and β-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 β-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and β-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and β-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 β-cell function.

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.

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia’s long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA1c levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.

SHEA, STEVEN, EVE AYMONG, PATRICIA ZYBERT, HARRY SHAMOON, RUSSELL P. TRACY, RICHARD J. DECKELBAUM, AND CHARLES E. BASCH. Obesity, fasting plasma insulin, and C-reactive protein levels in healthy children. Obes Res. 2003;11:95–103. Objective: Obesity is associated with hyperinsulinemia and increased level of C-reactive protein in older children and adults, but little is known about these relationships in very young children. We examined these relationships in healthy 2- to 3-year-old children. Research Methods and Procedures: Analyses were performed on data from 491 healthy 2- to 3-year-old Hispanic children enrolled in a dietary study conducted in New York City, 1992 to 1995. Results: Body mass index (BMI), ponderal index, and sum of four skinfolds were highly correlated (r 0.75) in both boys and girls. Fasting insulin and glucose levels were only modestly correlated (r 0.37 for boys and r 0.28 for girls; p 0.001 for both), but essentially all of the variability in a calculated index of insulin resistance was attributable to variability in fasting insulin level. The correlations of BMI with fasting insulin level were r 0.16 (p 0.05) in boys and r 0.14 (p 0.05) in girls. In separate multivariate regression analyses adjusting for age and sex, BMI and ponderal index were associated with fasting plasma insulin level (p 0.001 for both obesity measures). In multivariate regression analyses adjusting simultaneously for age, sex, and either BMI or ponderal index, fasting insulin level, but not these obesity measures, was associated with C-reactive protein level. Discussion: Obesity is associated with higher fasting insulin level, and fasting insulin is associated with C-reactive protein level, in healthy 2- to 3-year-old children.

As insulin sensitizers, thiazolidinediones could affect the hormonal counterregulatory response to hypoglycemia via the modulatory effect of insulin on counterregulation. In addition, recent studies suggest that thiazolidinediones may influence key steps in glucose sensing and glucoregulatory hormone secretion. We therefore evaluated the effects of a short course of troglitazone on counterregulatory hormones in response to mild hypoglycemia in eight lean nondiabetic subjects. Subjects received either troglitazone (400 mg/day) or placebo for 7 days before stepped hypoglycemia clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/L target plasma glucose steps, 50 min each). The glycemic thresholds for secretion of epinephrine (3.77 ± 0.05 mmol/L) and glucagon (3.83 ± 0.11 mmol/L) were reset to a higher plasma glucose concentration after troglitazone [4.05 ± 0.05 mmol/L (P = 0.003) and 4.10 ± 0.05 mmol/L (P = 0.03), respectively]. In addition, the magnitude of the rise in epinephrine and glucagon concentrations was hig...

OBJECTIVE To investigate the efficacy, safety, and dose-response characteristics of an extended-release preparation of glipizide using the gastrointestinal therapeutic system (GITS) on plasma glucose, glycosylated hemoglobin (HbA1c), and insulin secretion to a liquid-mixed meal in NIDDM patients. RESEARCH DESIGN AND METHODS Two prospective, randomized, double-blind, placebo-controlled, multicenter clinical trials were performed in 22 sites and 347 patients with NIDDM (aged 59 ± 0.6 years; BMI, 29 ± 0.3 kg/m2; known diabetes duration, 8 ± 0.4 years) were studied. Each clinical trial had a duration of 16 weeks with a 1-week washout, 3-week single-blind placebo phase, 4-week titration to a fixed dose, and 8-week maintenance phase at the assigned dose. In the first trial, once-daily doses of 5, 20, 40, or 60 mg glipizide GITS were compared with placebo in 143 patients. In the second trial, doses of 5, 10, 15, or 20 mg of glipizide GITS were compared with placebo in 204 patients. HbA1c, fasting plasma glucose (FPG), insulin, C-peptide, and glipizide levels were determined at regular intervals throughout the study. Postprandial plasma glucose (PPG), insulin, and C-peptide also were determined at 1 and 2 h after a mixed meal (Sustacal). RESULTS All doses of glipizide GITS in both trials produced significant reductions from placebo in FPG (range −57 to −74 mg/dl) and HbA1c (range −1.50 to −1.82%). Pharmacodynamic analysis indicated a significant relationship between plasma glipizide concentration and reduction in FPG and HbA1c over a dose range of 5–60 mg, with maximal efficacy achieved at a dose of 20 mg for FPG and at 5 mg for HbA1c. PPG levels were significantly lower, and both postprandial insulin and C-peptide levels significantly higher in patients treated with glipizide GITS compared with placebo. The percent reduction in FPG was comparable across patients with diverse demographic and clinical characteristics, including those with entry FPG ≥ 250 mg/dl, resulting in greater absolute decreases in FPG and HbA1c in patients with the most severe hyperglycemia. Despite the forced titration to a randomly assigned dose, only 11 patients in both studies discontinued therapy because of hypoglycemia. Glipizide GITS did not alter lipids levels or produce weight gain. CONCLUSIONS The once-daily glipizide GITS 1) lowered HbA1c, FPG, and PPG over a dose range of 5–60 mg, 2) was maximally effective at 5 mg (using HbA1c) or 20 mg (using FPG) based on pharmacokinetic and pharmacodynamic relationships, 3) maintained its effectiveness in poorly controlled patients (those with entry FPG ≥ 250 mg/dl), 4) was safe and well tolerated in a wide variety of patients with NIDDM, and 5) did not produce weight gain or adversely affect lipids.

We compared the effects of oral vanadyl sulfate (100 mg/day) in moderately obese NIDDM and nondiabetic subjects. Three-hour euglycemic-hyperinsulinemic (insulin infusion 30 mU · m−2 · min−1) clamps were performed after 2 weeks of placebo and 3 weeks of vanadyl sulfate treatment in six nondiabetic control subjects (age 37 ± 3 years; BMI 29.5 ± 2.4 kg/m2) and seven NIDDM subjects (age 53 ± 2 years; BMI 28.7 ±1.8 kg/m2). Glucose turnover ([3-3H]glucose), glycolysis from plasma glucose, glycogen synthesis, and whole-body carbohydrate and lipid oxidation were evaluated. Decreases in fasting plasma glucose (by ∼1.7 mmol/l) and HbAlc (both P < 0.05) were observed in NIDDM subjects during treatment; plasma glucose was unchanged in control subjects. In the latter, the glucose infusion rate (GIR) required to maintain euglycemia (40.1 ± 5.7 and 38.1 ± 4.8 μmol · kg fat-free mass [FFM]−1 · min−1) and glucose disposal (Rd) (41.7 ± 5.7 and 38.9 ±4.7 μmol · kg FFM−1 · min−1) were similar during placebo and vanadyl sulfate administration, respectively. Hepatic glucose output (HGO) was completely suppressed in both studies. In contrast, in NIDDM subjects, vanadyl sulfate increased GIR ∼82% (17.3 ± 4.7 to 30.9 ± 2.7 μmol · kg FFM−1 · min−1, P < 0.05); this improvement in insulin sensitivity was due to both augmented stimulation of Rd (26.0 ±4.0 vs. 33.6 ± 2.22 μmol · kg FFM−1 · min−1, P < 0.05) and enhanced suppression of HGO (7.7 ± 3.1 vs. 1.3 ± 0.9 μmol · kg FFM−1 · min−1, P < 0.05). Increased insulin-stimulated glycogen synthesis accounted for >80% of the increased Rd with vanadyl sulfate (P < 0.005), but plasma glucose flux via glycolysis was unchanged. In NIDDM subjects, vanadyl sulfate was also associated with greater suppression of plasma free fatty acids (FFAs) (P < 0.01) and lipid oxidation (P < 0.05) during clamps. The reduction in HGO and increase in Rd were both highly correlated with the decline in plasma FFA concentrations during the clamp period (P < 0.001). In conclusion, small oral doses of vanadyl sulfate do not alter insulin sensitivity in nondiabetic subjects, but it does improve both hepatic and skeletal muscle insulin sensitivity in NIDDM subjects in part by enhancing insulin's inhibitory effect on lipolysis. These data suggest that vanadyl sulfate may improve a defect in insulin signaling specific to NIDDM.

Objective To assess the plasma arterial catecholamine response to nocturnal desaturation in a group of patients with a history suggestive of sleep apnea. Patients and methods At a Veterans Affairs hospital, 10 patients who had a history consistent with sleep apnea syndrome were involved in the study. Arterial plasma catecholamines were measured at varying intervals during a 5 1/2-hour sleep study. Eighteen samples per patient were analyzed. Results As the hemoglobin saturation decreased, the variability in plasma norepinephrine increased significantly (r = -.78, P = 0.004). As the hemoglobin saturation fell, there was a trend towards higher concentrations of plasma norepinephrine (r = -.53, P = 0.06). As the hemoglobin saturation decreased, the variability in plasma epinephrine concentration was not significant (r = .42). Conclusion The association between the degree of desaturation and the variability in norepinephrine suggests that norepinephrine is released in response to nocturnal desaturation.

Quantitative sensory testing (QST) is commonly used in the assessment of diabetic neuropathy. However, little data are available on the reliability of tactile and thermal testing devices. Reproducibility of QST measures between centers has not been previously reported. This study was designed to validate QST testing procedures and determine if these devices are suitable for large scale multicenter clinical trials. Finger and toe vibratory (Vf, Vt) and thermal (Tf, Tt) thresholds were determined for ten normal individuals by a two-alternative forced-choice procedure using the Optacon Tactile Tester (OTT) and Thermal Sensitivity Tester (TST). Threshold measurements were reproducible between technologists and had a day-to-day coefficient of variation of Vf 20%, Vt 23%, Tf 41%, and Tt 95%. Thresholds were determined for 140 normal individuals at six centers. Mean threshold values between centers were not significantly different. Center-to-center coefficients of variation (CV) were Vf 44%, Vt 45%, Tf 47%, and Tt 87%. There was no significant difference in threshold measures with regard to sex, side studied, presence of calluses, or skin temperature. Vf thresholds significantly correlated with age (p < 0.01). There was no correlation between either vibratory or thermal thresholds in normal individuals, and nerve conduction velocities (NCV). Thermal and vibratory thresholds were determined for 98 diabetic patients. Diabetic subjects without clinical evidence of neuropathy were not significantly different from normal individuals, but diabetic patients with neuropathy had increased thresholds compared to normals (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The charts of 254 Hispanic patients were selected from a sample of 321 patients with diabetes in four urban clinics that received federal funding to provide medical care in underserved communities. A standardized chart-audit protocol was used to assess the process of healthcare delivery and the presence of diabetes-associated comorbidities and complications in patients. Inconsistent recognition of obesity (11% identified vs 59% present), hyperlipidemia (17% identified vs 69% present), and renal dysfunction (3.5% identified vs 16% present) was evident on chart review. We also found inadequate compliance with current recommendations for diabetes care with respect to routine health screenings for diabetes-related complications, recognition of comorbid diagnoses, and referral of patients for recommended specialty consultations. Issues specific to the varied Hispanic populations may need to be considered to improve the delivery of diabetes care for the growing Hispanic population with diabetes.

OBJECTIVE To describe the methods used to implement intensive and conventional therapies in the Diabetes Control and Complications Trial (DCCT) and the metabolic results that occurred with the different treatment regimens. RESEARCH DESIGN AND METHODS The DCCT was a controlled clinical trial that demonstrated the beneficial effect of intensive therapy on the long-term complications of insulin-dependent diabetes mellitus (IDDM). A total of 1,441 volunteers with IDDM, aged 13–39, from 29 centers in the U.S. and Canada, were randomly assigned to conventional or intensive diabetes therapy. Intensive therapy, which used multiple daily injections (MDI) of insulin (≥3 injections/day) or continuous subcutaneous insulin infusion (CSI1), was implemented by a team that included diabetes nurses, dietitians, behavioral experts, and diabetologists. Volunteers in the intensive treatment group could use MDI or CSII, based on patient and clinic preference, and could switch between therapies over the course of the study. The volunteers were followed for a mean of 6.5 years (range 3–9 years). RESULTS A detailed analysis of implementation of the two treatments indicates that intensive and conventional treatment subjects adhered to their respective insulin injection regimens >97% of the time. Adherence to other elements of intensive treatment was similarly high and resulted in median HbAlc values between 6.7 and 7.2, compared with 8.7–9.2 with conventional therapy, over the course of the study. Severe hypoglycemia occurred three times more often in intensively treated subjects. Although subjects on intensive treatment were not randomly assigned to MDI or CSII, we compared those subjects who used either of these methods for >90% of the study time. CSIIy-treated patients maintained a mean HbAlc of 6.8 vs. 7.0 in MDI-treated subjects during the trial (P < 0.05). The frequency of hypoglycemia with coma and seizure and diabetic ketoacidosis was modestly higher with CSII than with MDI. CONCLUSIONS Intensive therapy was implemented successfully in the DCCT. The detailed description herein will serve to facilitate translation of the DCCT results to the clinical setting.

Background The established guidelines for a diabetes foot examination include assessing circulatory, skin, and neurological status to detect problems early and reduce the likelihood of amputation. Objective To determine documented adherence with guidelines for foot examinations. Setting Four clinics in underserved areas. Methods Charts of 350 diabetic patients, identified by billing code, were reviewed for foot examination documentation. A documented foot examination was defined as assessing at least two of the three components of a foot examination. The review determined the periodicity and prevalence of foot examinations, referrals to a podiatrist or vascular surgeon during a 2-year period, and risk factors for foot complications. Stepwise logistic regression was used to determine whether risk factors for foot complications predicted foot examination status. Results The patients had a mean age and duration of diabetes of 57.7 and 8.8 years, respectively; 86% were black or Hispanic. There was no indication of foot examination or referral for 55.7% of the patients during the 2-year period. Patients with foot care referrals were more likely to have foot examinations by their primary care providers (P = .0001). There was almost a fourfold increase in the odds that patients with diagnosed peripheral vascular disease had foot examinations, with twofold greater odds for each 25-year increase in age. Conclusions Populations at risk of diabetic complications are unlikely to have foot examinations in their primary medical care, but having peripheral vascular disease increases the likelihood. Efforts are needed to improve adherence to foot examination guidelines for patients with diabetes from underserved populations.

The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic and discoveries to clinical practice, ultimately improving the health of the nation. The 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 C&T science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support.

Patients with intensively treated insulin-dependent diabetes mellitus (IDDM) exhibit more severe defects in counterregulatory hormone secretion and symptom recognition during hypoglycemia than do conventionally treated patients. In this prospective study in patients with preexisting defects in counterregulation, we examined the induction and reversibility of impaired symptomatic and adrenomedullary responses to hypoglycemia in 5 patients with IDDM (diabetes duration of 2 to 16 years; aged 19 to 36 years; 3 women, 2 men) who were receiving intensive therapy.Counterregulatory responses were assessed by using a single-step (approximately 2.8 mmol/L plasma glucose) and multiple-step (from approximately 5 mmol/L to 2.2 mmol/L plasma glucose) clamped hypoglycemia procedure. Patients were first studied after a stable period of conventional insulin therapy (glycosylated hemoglobin [HbA1c] 9.5 +/- 1.2%), then after 3 to 5 months of intensive therapy (HbA1c 6.6 +/- 0.2%), and a third time after resuming conventional therapy (HbA1c 8.7 +/- 0.9%).Intensive therapy was associated with a 44% decline (P0.01) in the average plasma epinephrine increase during hypoglycemia, and the plasma glucose level required to stimulate epinephrine secretion fell from 3.7 +/- 0.2 to 3.0 +/- 0.1 mmol/L (P0.01). The threshold, but not the magnitude, of the plasma norepinephrine response was similarly altered. Hypoglycemic symptoms also decreased in intensity (by 67%, P0.01), and the glucose level required for symptom activation fell from 3.4 +/- 0.3 to 2.7 +/- 0.2 mmol/L, P0.01). When conventional therapy was resumed, the abnormalities in the epinephrine response due to intensive therapy were almost completely reversed. However, the reduction in symptoms and the altered thresholds for plasma norepinephrine were not reversed.There is dissociation between the treatment-associated defects in hypoglycemia counterregulation in IDDM, and an increase in average glycemia produced by a return to conventional insulin therapy is not sufficient to reverse hypoglycemia unawareness worsened by intensive therapy.

We evaluated skeletal muscle counterregulation during hypoglycemia in nine subjects with non-insulin-dependent diabetes mellitus (NIDDM) (HbA1c 9.4 +/- 0.5%, nl < 6.2%) compared with six normal controls, matched for age (51 +/- 3 and 49 +/- 5 yr, respectively) and body mass index (27.3 +/- 1.2 and 27.0 +/- 2.1 kg/m2). After 60 min of euglycemia (plasma insulin approximately 140 microU/ml), plasma glucose was lowered to 62 +/- 2 mg/dl by 120 min. Hypoglycemia induced a 2.2-fold greater increase in plasma epinephrine in NIDDM (P < 0.001), while the plasma glucagon response was blunted (P < 0.01). Hepatic glucose output ([3H-3]glucose) suppressed similarly during euglycemia, but during hypoglycemia was greater in NIDDM (P < 0.005). Conversely, glucose uptake during euglycemia was 150% greater in controls (P < 0.01) and remained persistently higher than in NIDDM during hypoglycemia. In NIDDM, plasma FFA concentrations were approximately fivefold greater (P < 0.001), and plasma lactate levels were approximately 40% higher than in controls during hypoglycemia (P < 0.01); the rates of glycolysis from plasma glucose were similar in the two groups despite a 49% lower rate of glucose uptake in NIDDM (3.4 +/- 0.9 vs. 6.9 +/- 1.3 mg/kg per minute, P < 0.001). Muscle glycogen synthase activity fell by 42% with hypoglycemia (P < 0.01) in NIDDM but not in controls. In addition, glycogen phosphorylase was activated by 56% during hypoglycemia in NIDDM only (P < 0.01). Muscle glucose-6-phosphate concentrations rose during hypoglycemia by a twofold greater increment in NIDDM (P < 0.01). Thus, skeletal muscle participates in hypoglycemia counterregulation in NIDDM, directly by decreased removal of plasma glucose and, indirectly, by providing lactate for hepatic gluconeogenesis. Consequently, in addition to inherent insulin resistance in NIDDM, the enhanced plasma epinephrine response during hypoglycemia may partially offset impaired glucagon secretion and counteract the effects of hyperinsulinemia on liver, fat, and skeletal muscle.

We evaluated the effect of continuous physiological hyperinsulinemia on counterregulatory hormone responses in seven healthy subjects, each studied on two occasions. Hormone responses were measured during identical 2-h periods of hypoglycemia (plasma glucose target 3.5 mmol/L) at insulin levels of 350 pmol/L or 640 pmol/L. During hypoglycemia, there were significant (50-1400%) increases in glucagon, epinephrine, norepinephrine, GH, and cortisol which were comparable in the two groups. We further evaluated the influence of the duration of mild hyperinsulinemia on the responses in an additional group of normal subjects (n = 7). Brief (30 min) exposure to insulin was compared to a prolonged (3.5 h) insulin infusion, each followed by identical hypoglycemia. Plasma insulin (approximately 350 pmol/L) and plasma glucose (target 3.3 mmol/L) were similar in both groups. The increases in epinephrine, norepinephrine, GH, and cortisol during hypoglycemia were virtually identical in the two groups. However, the secretion of glucagon was blunted following prolonged hyperinsulinemia, increasing to levels of 249 +/- 17 ng/L in the brief studies and to only 185 +/- 20 ng/L in the prolonged studies (P0.005). The insulin-induced decrement in plasma amino acids were similar in the two studies and could not account for the impaired glucagon secretory response.1) Brief exposure to even high physiological levels of insulin do not alter the magnitude of counterregulatory hormone secretion during hypoglycemia; 2) prolonged hyperinsulinemia results in a selective blunting of the plasma glucagon response to hypoglycemia, perhaps due to a direct suppressive effect of insulin on alpha-cell secretion.

Recent developments in epidemiology, physiology, anatomy and molecular biology have greatly increased our knowledge of the aetiology and immunological mechanisms involved in diabetes mellitus. This understanding has, in turn, facilitated progress in the diagnosis and treatment of the disease. It is generally accepted that both genetic and environmental factors have a role in the pathogenesis of insulin- and non-insulin-dependent diabetes mellitus. The contribution of insulin resistance or decreased insulin secretion to the pathogenesis of non-insulin-dependent diabetes remains controversial but it is likely that both have a role to play. Counterregulatory hormones, principally adrenaline (epinephrine) and glucagon, prevent blood glucose levels falling to extreme levels by antagonising the effect of insulin hypoglycaemia, and inducing hepatic glucose production. Patients with insulin-dependent diabetes frequently exhibit impaired glucose counterregulation and, although its aetiology is uncertain in some patients, intensification of insulin therapy per se has been implicated. Secondary failure of oral hypoglycaemic agents in patients with non-insulin-dependent diabetes is a major and often inevitable problem, necessitating combined use of sulphonylurea and insulin in most patients. Recently, new treatments for patients with diabetes have been developed, including insulin analogues administered by a variety of novel methods, pancreatic grafts and transplantation of islet cells. Although promising, the clinical viability of these techniques remains to be demonstrated.

57 TWO DECADES HAVE PASSED since the introduction of self-monitoring of blood glucose (SMBG) into diabetes management for people with type 1 diabetes. The daily, periodic sampling of capillary blood glucose has facilitated rational use of algorithms for insulin dose adjustment, more prompt and judicious treatment of hyperglycemia and hypoglycemia, and better integration of diet and exercise variations in treatment regimens. With greater frequency of SMBG, there is greater potential for the adaptation of treatment to the changing needs of the person with diabetes. Most importantly, SMBG has been the cornerstone of intensive therapy that aims at maintaining blood glucose close to the normal range. The Diabetes Control and Complications Trial (DCCT) established that intensive therapy can prevent and/or slow the development of microvascular complications in type 1 diabetes, but the DCCT also highlighted the risk of attendant hypoglycemia,1,2 despite SMBG four or more times daily. Several factors may lead to the increased risk of both moderate (self-treatable) or severe (requiring assistance) hypoglycemia. First and foremost, current insulin replacement techniques are imperfect, and inappropriate hyperinsulinemia leads to suppression of endogenous glucose output and increase of glucose uptake. Exercise, decreased food intake, missed meals, alcohol ingestion, and other factors exacerbate the metabolic demands imposed by hyperinsulinemia. However, it has become clear that additional factors leading to an increased risk of severe hypoglycemia are defective glucose counterregulation and impaired hypoglycemia awareness.3 Defective counterregulation in type 1 diabetes is due to the combined impairment in secretion of epinephrine and glucagon. Defects in epinephrine secretion with intensive therapy are likely to be due, in part, to frequent iatrogenic hypoglycemia, and efforts at reducing the frequency of hypoglycemia may reverse the defect in epinephrine response.4–9 Thus, in addition to allowing the patient to identify and anticipate hypoglycemia, more frequent measurement of blood glucose may reduce the number of mild or symptomatic hypoglycemia episodes that lead to severe hypoglycemia events. However, blood glucose sampling has several perceived and real disadvantages that have stimulated the search for alternative means of assessing glycemia. Concerns that have been raised about current SMBG techniques include the need for skin lancing and the practical limitations of obtaining samples frequently enough to permit closed-loop insulin replacement. Frequent monitoring of glucose with a sensor in contact with the bloodstream, while conceptually ideal, presents a number of prac

Repeated hypoglycemia is associated with hypoglycemia-associated autonomic failure (HAAF), a syndrome of defective counterregulation.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.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+).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, P0.01), as well as in endogenous glucose production (24 vs. 163%; P0.01). 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 (PNS for all). Infusion of naloxone alone during euglycemia on d 1 (C+) had no effect on d 2 responses.These data suggest that the opioid signaling system is a promising target for further studies to prevent HAAF.

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 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 μg/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.

Objective To describe the practice of quality assurance (QA) for capillary blood glucose monitoring (CBGM) in health-care facilities. Research Design and Methods Descriptive survey data were collected from a purposive sample of 378 health-care providers, who use CBGM and direct CBGM QA programs, from acute- and chronic-care facilities in 47 states. Subjects completed a 36-item multiple-choice survey about QA practices for CBGM by providers. Results Only 53.4% of respondents reported a multidisciplinary advisory group to assist in decision making for the CBGM program. Almost one-third reported no clinical laboratory involvement in their QA program. Over 70% of respondents reported inclusion of all clinical areas in the CBGM program. Comparison of results of the same patient sample by laboratory reference method and CBGM system was done routinely by only 43.6% of respondents. Scheduled proficiency testing was reported by 33.4%. Only 5.8% of respondents reported the coexistence of a CBGM advisory group, full participation of the laboratory, and quarterly proficiency testing. Over 50% of respondents reported a patient charge for CBGM. Conclusions When survey results are compared with regulatory and accreditation standards, it is evident that a wide gap exists. Resources to bridge this gap may be scarce in many facilities. Further research is needed to determine minimal QA standards for CBGM that provide for optimal patient outcomes.

The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes.We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo).This study included 3548 Diabetes Prevention Program participants.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.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.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.

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 (HbA1c 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 ([3-3H]-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 μmol · 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.

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.

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.

Glucose effectiveness is impaired in type 2 diabetes. We hypothesize that chronic hyperglycemia and hyperlipidemia contribute importantly to this defect. To test this hypothesis, we compared the effect of acute hyperglycemia on glucose turnover in type 2 diabetic subjects in good control (GC) (n = 14, age 51.7 +/- 3.7 years, BMI 28.4 +/- 1.0 kg/ m(2), HbA(1c) 5.9 +/- 0.2%) and poor control (PC) (n = 10, age 50.0 +/- 2.5 years, BMI 27.9 +/- 1.5 kg/m(2), HbA(1c) 9.9 +/- 0.6%) with age- and weight-matched nondiabetic subjects (ND) (n = 11, age 47.0 +/- 4.4 years, BMI 28.5 +/- 1.0 kg/m(2), HbA(1c) 5.1 +/- 0.2%). Fixed hormonal conditions were attained by infusing somatostatin for 6 h with replacement of basal insulin, glucagon, and growth hormone. Glucose fluxes ([3-(3)H]glucose) were compared during euglycemic (5 mmol/l, t = 180-240 min) and hyperglycemic (Hy) (10 mmol/l, t = 300-360 min, variable glucose infusion) clamp intervals. Acute hyperglycemia suppressed hepatic glucose production (GP) by 43% and increased peripheral glucose uptake (GU) by 86% in the ND subjects. Conversely, GP failed to suppress (-7%) and GU was suboptimally increased (+34%) in response to Hy in the PC group. However, optimal glycemic control was associated with normal glucose effectiveness in GC subjects (GP -38%, GU +72%; P > 0.05 for GC vs. ND). To determine whether short-term correction of hyperglycemia and/or hyperlipidemia is sufficient to reverse the impairment in glucose effectiveness, five PC subjects were restudied after 72 h of normoglycemia ( approximately 100 mg/dl; variable insulin infusions). These subjects regained normal effectiveness of glucose to suppress GP and stimulate GU and in response to Hy (GP -47%, GU + 71%; P > 0.05 vs. baseline studies). Thus, chronic hyperglycemia and/or hyperlipidemia contribute to impaired effectiveness of glucose in regulating glucose fluxes in type 2 diabetes and hence to worsening of the overall metabolic condition. Short-term normalization of plasma glucose might break the vicious cycle of impaired glucose effectiveness in type 2 diabetes.

We evaluated the effect of physiologic hyperinsulinemia (plasma insulin 329 +/- 62 vs 687 +/- 62 pmol/L) on counterregulatory hormone responses in 8 IDDM subjects studied during a 2-hour hypoglycemic clamp study with an equivalent degree of hypoglycemia (plasma glucose 3.1 +/- 0.1 and 3.0 +/- 0.1 mmol/L, respectively). Plasma epinephrine levels were increased by 71% during the last 60 minutes of hypoglycemia in the high insulin study (840 +/- 180 vs 1440 +/- 310 pmol/L, respectively p = 0.006). In addition, plasma cortisol and norepinephrine were also increased in the high insulin study (by 19% and 24% respectively, p0.01, for both). Plasma growth hormone and glucagon concentrations were not altered by high dose insulin infusion. In spite of increased epinephrine secretion, the glucose infusion rate required to maintain glucose was 2-fold greater in the high insulin study, and there was greater suppression of lipolysis in that group. We conclude that hyperinsulinemia may enhance counterregulatory hormone secretion in IDDM.

OBJECTIVES: This study evaluated a multicomponent educational intervention to increase ophthalmic examination rates among African Americans with diabetes. METHODS: A randomized trial was conducted with 280 African Americans with diabetes, enrolled from outpatient departments of 5 medical centers in the New York City metropolitan area, who had not had a dilated retinal examination within 14 months of randomization (65.7% female, mean age = 54.7 years [SD = 12.8 years]). RESULTS: After site differences were controlled, the odds ratio for receiving a retinal examination associated with the intervention was 4.3 (95% confidence interval = 2.4, 7.8). The examination rate pooled across sites was 54.7% in the intervention group and 27.3% in the control group. CONCLUSIONS: The intervention was associated with a rate of ophthalmic examination double the rate achieved with routine medical care.

OBJECTIVE: To analyze a transcutaneous near-infrared spectroscopy system as a technique for in vivo noninvasive blood glucose monitoring during euglycemia and hypoglycemia. RESEARCH DESIGN AND METHODS: Ten nondiabetic subjects and two patients with type 1 diabetes were examined in a total of 27 studies. In each study, the subject's plasma glucose was lowered to a hypoglycemia level (approximately 55 mg/dl) followed by recovery to a glycemic level of approximately 115 mg/dl using an intravenous infusion of insulin and 20% dextrose. Plasma glucose levels were determined at 5-min intervals by standard glucose oxidase method and simultaneously by a near-infrared spectroscopic system. The plasma glucose measured by the standard method was used to create a calibration model that could predict glucose levels from the near-infrared spectral data. The two data sets were correlated during the decline and recovery in plasma glucose, within 10 mg/dl plasma glucose ranges, and were examined using the Clarke Error Grid Analysis. RESULTS: Two sets of 1,704 plasma glucose determinations were examined. The near-infrared predictions during the fall and recovery in plasma glucose were highly correlated (r = 0.96 and 0.95, respectively). When analyzed during 10 mg/dl plasma glucose segments, the mean absolute difference between the near-infrared spectroscopy method and the chemometric reference ranged from 3.3 to 4.4 mg/dl in the nondiabetic subjects and from 2.6 to 3.8 mg/dl in the patients with type 1 diabetes. Using the Error Grid Analysis, 97.7% of all the near-infrared predictions were assigned to the A-zone. CONCLUSIONS: Our findings suggest that the near-infrared spectroscopy method can accurately predict plasma glucose levels during euglycemia and hypoglycemia in humans.

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.

Unlabelled BACKGROUND. Changes in the sympathetic nervous system may be a cause of postoperative cardiovascular complications. The authors hypothesized that changes in both beta-adrenergic receptor (betaAR) function (as assessed in lymphocytes) and in sympathetic activity (assessed by plasma catecholamines and by heart rate variability [HRV] measurements obtained from Holter recordings) occur after operation. Methods The HRV parameters were measured in 28 patients having thoracotomy (n = 14) or laparotomy (n = 14) before and for as long as 6 days after operation. Transthoracic echocardiography was performed before and on postoperative day 2. Lymphocytes were also isolated from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). They were used to examine betaAR number (Bmax) and cyclic adenosine monophosphate (cAMP) production after stimulation with isoproterenol and prostaglandin E1. In addition, plasma epinephrine, norepinephrine, and cortisol concentrations were determined at similar intervals. Results After abdominal and thoracic surgery, most time and all frequency indices of HRV decreased significantly, as did Bmax and basal and isoproterenol-stimulated cAMP production. The decrements in HRV correlated with those of Bmax and isoproterenol-stimulated cAMP throughout the first postoperative week and inversely correlated with the increase in heart rate. Plasma catecholamine concentrations did not change significantly from baseline values, but plasma cortisol levels did increase after operation in both groups. Left ventricular ejection fraction was normal in both groups and unaffected by surgery. Conclusions Persistent downregulation and desensitization of the lymphocyte betaAR/adenylyl cyclase system correlated with decrements in time and frequency domain indices of HRV throughout the first week after major abdominal or thoracic surgery. These physiologic alterations suggest the continued presence of adaptive autonomic regulatory mechanisms and may explain why the at-risk period after major surgery appears to be about 1 week or more.

Diabetes-related ophthalmic complications are the leading cause of newly diagnosed blindness among adults. These eye complications are often asymptomatic in the early stages, yet the majority of diabetes patients are not screened yearly. To develop a health promotion intervention to increase the rate of screening for diabetic retinopathy by dilated fundus exam (DFE), we assessed the knowledge and health beliefs related to preventing diabetic eye complications among a sample of African-Americans with diabetes. The study design was cross-sectional, using a telephone interview to collect data. From a random sample of 104 African-Americans with diabetes, 67 (64%) were completed: 54 women; mean age of 58 years. The telephone interview schedule contained items grouped into subscales for Perceived Incentives, Perceived Barriers to getting a DFE, Causes of Eye Problems, Risk of Eye Problems, and Effective Treatments for Eye Problems. Descriptive statistics were used to analyze the quantitative data. Transcribed qualitative responses to the open-ended questions were analyzed for themes. The incentives “having eye problems” and “doctor said it was important to go” each had 91% responding it was an incentive to go for a DFE. Only about one-third agreed that any particular item was a barrier to receiving a DFE (e.g., economic factors). In the subscale for Risk of Eye Problems, “retinopathy” had the lowest level of perceived risk (30%). Only 21% of the sample reported there were effective treatments for retinopathy. Eighty-seven percent reported the faulty belief that “diabetic eye problems have symptoms.” Only 36% of the sample said they had heard of retinopathy and of those, only 8% could describe it correctly. Among general response themes were: fear, spirituality (faith and hope), priorities, economic or logistical factors, and external/internal motivation. Perceived incentives for receiving a DFE were acknowledged at far greater rates than perceived barriers. Having a yearly DFE in the absence of symptoms must be emphasized in health promotion materials. There are effective, early treatments for diabetic eye problems, and this information should be used to counter the fear of a dreaded diagnosis with the hope of treatment and cure. Ways of coping with fear of having the exam should be included in health education. DFEs must become a routine yearly exam and not just a reaction to recognized problems. Health education must address the specific needs of high-risk minority populations.

The level of adherence with recommended standards for ophthalmic examinations was assessed in a purposive sample of diabetic patient charts (n = 350) from four clinics in medically underserved areas. All of the clinics referred patients with diabetes to off-site services for comprehensive eye examinations (dilation, visual acuity, and intraocular pressure); adherence with the standard of care was defined as a chart note indicating a referral for an ophthalmic examination. Overall, 86% of the patients were from high-risk minority groups (black or Hispanic) for diabetes and its complications. Mean age and duration of diabetes were 57.7 and 8.8 years, respectively. Referrals for ophthalmic exams were noted in 18% of the charts during the year preceding the review and in 28.6% of the charts during the 2 preceding years. Annual referrals in the preceding 2 years were noted in 3.1% of the charts. Eye disease was noted as a diagnosis in 22%. Patients who had a diagnosis of eye disease noted in their charts had a 7.5-fold increase in the odds of having a referral noted. The increased likelihood of being referred in patients with known eye disease may be due to follow-up of current eye problems.

Iatrogenic hypoglycemia causes recurrent physical and recurrent or even persistent psychosocial morbidity, and some mortality, in patients with insulindependent diabetes mellitus (IDDM), and in some patients with non-insulin-dependent diabetes mellitus (NIDDM) (1,2). There is now compelling evidence, from the Diabetes Control and Complications Trial (DCCT), that metabolic control delays the development and progression of retinopathy, nephropathy and neuropathy in IDDM, albeit at the expense of an increased frequency of treatment-induced hypoglycemia (3). These findings will almost assuredly provide further impetus to patients and health care providers to attempt to maintain plasma glucose levels as close to the nondiabetic range as possible. If so, hypoglycemia will become an even more common problem for patients with diabetes in the near future.

OBJECTIVE To determine whether reduced hormonal, symtomatic, and/or cognitive responses to hypoglycemia are caused by an increase in the plasma glucose concentration required to stimulate these counterregulatory parameters after antecedent hypoglycemia. RESEARCH DESIGN AND METHODS We studied nine healthy volunteers during stepped hypoglycemia clamps (plasma glucose targets from 80 to 50 mg/dl in 10 mg/dl steps) on two separate days. The study was preceded either by a 2-h period of hypoglycemia (plasma glucose 58 ± 2 mg/dl) or a 2-h period of euglycemia (plasma glucose 94 ± 2 mg/dl) for 90 min. RESULTS The plasma glucose that triggered secretion of-plasma norepinephrine (NE) was lower after antecedent hypoglycemia (control = 74 ± 2 and experimental = 67 ± 2 mg/dl, respectively, P < 0.005). In contrast, a relatively higher plasma glucose stimulated secretion of other counterregulatory hormones after anteceden hypoglycemia: growth hormone (GH) (65 ± 2 to 72 ± 2 mg/dl, P < 0.01); glucagon (63 ± 2 to 70 ± 2 mg/dl, P < 0.01); and epinephrine (EPI) (68 ± 2 to 76 ± 2 mg/dl, P < 0.01) when comparing control days with experimental days. Hypoglycemic symptoms were first observed at a plasma glucose plateau of 59 ± 2 mg/dl. Motor function reflected by Digit Symbol Substitution deteriorated equally whether there had been antecedent hypoglycemia or euglycemia. Logical (immediate) memory deteriorated in the control study at a plasma glucose of 54 ± 2 mg/dl but remained unchanged at equivalent hypoglycemia in the experimental study (P / 0.03). CONCLUSIONS Our conclusions are as follows: 1) symptoms of moderate hypoglycemia occur at plasma glucose levels averaging ∼5-15 mg/dl lower than the plasma glucose concentrations required to trigger counterregulatory hormone release; 2) after acute antecedent hypoglycemia, glucagon, EPI, and GH secretion occur at higher plasma glucose concentrations and NE is released at lower plasma glucose concentrations; and 3) there may be CNS adaptation to prior hypoglycemia reflected in preservation of logical memory function at plasma glucose levels of ∼50 mg/dl. These findings suggest that thresholds for hormone secretion and for changes in cognitive function can be altered very acutely by foregoing hypoglycemia in healthy humans.