Plasma acylcarnitines during insulin stimulation in humans are reflective of age-related metabolic dysfunction.

The purpose of this study was to determine if plasma acylcarnitine (AC) profiling is altered under hyperinsulinemic conditions as part of the aging process. Fifteen young, lean (19-29 years) and fifteen middle-to older-aged (57-82 years) individuals underwent a 2-hr euglycemic-hyperinsulinemic clamp. Plasma samples were obtained at baseline, 20 min, 50 min, and 120 min for analysis of AC species and amino acids. Skeletal muscle biopsies were performed after 60 min of insulin-stimulation for analysis of acetyl-CoA carboxylase (ACC) phosphorylation. Insulin infusion decreased the majority of plasma short-, medium-, and long-chain (SC, MC, and LC, respectively) AC. However, during the initial 50 min, a number of MC and LC AC species (C10, C10:1, C12:1, C14, C16, C16:1, C18) remained elevated in aged individuals compared to their younger counterparts indicating a lag in responsiveness. Additionally, the insulin-induced decline in skeletal muscle ACC phosphorylation was blunted in the aged compared to young individuals (-24% vs. -56%, P < 0.05). These data suggest that a desensitization to insulin during aging, possibly at the level of skeletal muscle ACC phosphorylation, results in a diminished ability to transition to glucose oxidation indicative of metabolic inflexibility.

Glucose variability is an independent predictor of mortality in hospitalized patients treated with total parenteral nutrition.

OBJECTIVE: Hyperglycemia is associated with increased mortality in critically ill patients treated with total parenteral nutrition (TPN). The role of glucose variability (GV) in predicting outcomes in these patients is not known. METHODS: This retrospective study included medical and surgical patients receiving TPN in a community teaching hospital. GV was calculated by standard deviation (SD) of blood glucose (BG) values and by mean BG daily (Δ) change (daily max - daily minimum). RESULTS: A total of 276 medical and surgical patients (mean age: 51 ± 18 years), 19% with a history of diabetes mellitus (DM), and 74% with intensive care unit (ICU) admission were treated with TPN. During TPN, the mean daily BG was 142.9 ± 33 mg/dL; frequencies of hypoglycemia < 70 and < 40 mg/dL were 41% and 3%, respectively; and hospital mortality was 27.2%. The mean GV by SD was 38 ± 21 mg/dL and by mean (D) change 58 ± 34 mg/dL. GV was significantly higher in deceased patients (SD: 48 ± 25 vs. 34 ± 18 mg/dL and Δ change: 75 ± 39 vs. 51 ± 29 mg/dL, both P < .01) than surviving patients. Multivariate analysis adjusted for age, DM status, gender, APACHE (Acute Physiology and Chronic Health Evaluation) score, mean daily glucose, and hypoglycemia revealed that GV was an independent predictor of hospital mortality (P < .05). The association between GV and mortality was limited to patients without a history of DM and was not present in patients with DM. CONCLUSION: High GV is associated with increased hospital mortality independent of the presence and severity of hyperglycemia or hypoglycemia during TPN therapy. Prospective randomized trials are needed to determine if reduction in GV with intensive glycemic control improves clinical outcomes in patients treated with TPN.

A double-blind, randomized clinical trial comparing soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit patients requiring parenteral nutrition.

OBJECTIVE: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. PATIENTS: Adult medical-surgical intensive care unit patients. INTERVENTION: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions. MEASUREMENTS: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. RESULTS: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. CONCLUSION: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults.

Primary care fellowship in diabetes: an innovative program in postgraduate diabetes education.

BACKGROUND: To address the need of caring for the growing number of patients with diabetes, East Carolina University implemented a 1-year fellowship in diabetes. Most of the region has been designated as Health Professional Shortage Areas. DESCRIPTION: The objective of the fellowship is to educate primary care physicians to serve as regional specialists in diabetes. The program is administered by physicians, educators, and representatives of the university's affiliated teaching hospital. The curriculum includes clinical, didactic, and experiential learning strategies in outpatient and inpatient settings. Adult and pediatric endocrinologists, obstetricians, and generalists mentor and evaluate the fellows. EVALUATION: This innovative training program has improved the availability of high-quality diabetes care for underserved patients in the region. Mean glycemic control in fellows' patients improved and other clinical endpoints were also met. CONCLUSIONS: A 1-year diabetes fellowship is a replicable solution to address the need for diabetes care specialists.

The Yin and Yang Between Plasma Glucose Levels and Cortisol Replacement Therapy in Schmidt's Syndrome.

Objective: To illustrate how steroid replacement in adrenal insufficiency can influence the development of hypoglycemia in a patient with type 1 diabetes mellitus (T1D). Methods: We describe the case of a 36-year-old female patient with T1D and Addison's disease (Schmidt's syndrome) on multiple daily insulin injections who presented with recurrent hypoglycemia despite being on physiological replacement doses of hydrocortisone. Results: With the assistance of continuous glucose monitoring technology, a pattern of nocturnal hypoglycemia was clearly identified. The patient was taking her hydrocortisone 15 mg in the morning and 5 mg in the early afternoon. With the short half-life of oral hydrocortisone, the evening decline in plasma cortisol concentration led to an increased susceptibility to recurrent evening and nocturnal hypoglycemia. Hypoglycemic episodes were resolved when her morning hydrocortisone dose was changed and prednisolone was added to a later time in the evening. Conclusion: Patients with Schmidt's syndrome can be susceptible to nocturnal hypoglycemia with inadequate steroid replacement. Identifying patients at risk for hypoglycemia in Schmidt's syndrome provides an opportunity for precision management beyond the manipulation of antihyperglycemic agents.

Financial implications of glycemic control: results of an inpatient diabetes management program.

OBJECTIVE: (1) To determine the financial implications associated with changes in clinical outcomes resulting from implementation of an inpatient diabetes management program and (2) to describe the strategies involved in the formation of this program. METHODS: The various factors that influence financial outcomes are examined, and previous and current outcomes are compared. RESULTS: Associations exist between hyperglycemia, length of stay, and hospital costs. Implementation of an inpatient diabetes management program, based on published guidelines, has been shown to increase the use of scheduled medications to treat hyperglycemia and increase the frequency of physician intervention for glucose readings outside desired ranges. Results from implementing this program have included a reduction in the average glucose level in the medical intensive care unit through use of protocols driven to initiate intravenous insulin once the glucose level exceeds 140 mg/dL. Additionally, glucose levels have been reduced throughout the hospital, primarily because of interactions between diabetes nurse care managers and the primary care team. Associated with these lower glucose levels are a decreased prevalence of central line infections and shorter lengths of stay. The reduction in the length of stay for patients with diabetes has resulted in a savings of more than 2 million dollars for the year and has yielded a 467% return on investment for the hospital. CONCLUSION: Improved blood glucose control during the hospitalization of patients with known hyperglycemia is associated with reduced morbidity, reduced hospital length of stay, and cost savings. The implementation of an inpatient diabetes management program can provide better glycemic control, thereby improving outcomes for hyperglycemic patients while saving the hospital money.

Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences.

BACKGROUND: Diabetic ketoacidosis (DKA), once thought to typify type 1 diabetes mellitus, has been reported to affect individuals with type 2 diabetes mellitus. An analysis and overview of the different clinical and biochemical characteristics of DKA that might be predicted between patients with type 1 and type 2 diabetes is needed. METHODS: We reviewed 176 admissions of patients with moderate-to-severe DKA. Patients were classified as having type 1 or type 2 diabetes based on treatment history and/or autoantibody status. Groups were compared for differences in symptoms, precipitants, vital statistics, biochemical profiles at presentation, and response to therapy. RESULTS: Of 138 patients admitted for moderate-to-severe DKA, 30 had type 2 diabetes. A greater proportion of the type 2 diabetes group was Latino American or African American (P<.001). Thirty-five admissions (19.9%) were for newly diagnosed diabetes. A total of 85% of all admissions involved discontinuation of medication use, 69.2% in the type 2 group. Infections were present in 21.6% of the type 1 and 48.4% of the type 2 diabetes admissions. A total of 21% of patients with type 1 diabetes and 70% with type 2 diabetes had a body mass index greater than 27. Although the type 1 diabetes group was more acidotic (arterial pH, 7.21 +/- 0.12 vs 7.27 +/- 0.08; P<.001), type 2 diabetes patients required longer treatment periods (36.0 +/- 11.6 vs 28.9 +/- 8.9 hours, P =.01) to achieve ketone-free urine. Complications from therapy were uncommon. CONCLUSIONS: A significant proportion of DKA occurs in patients with type 2 diabetes. The time-tested therapy for DKA of intravenous insulin with concomitant glucose as the plasma level decreases, sufficient fluid and electrolyte replacement, and attention to associated problems remains the standard of care, irrespective of the type of diabetes.

Randomized Controlled Trial of Intensive Versus Conservative Glucose Control in Patients Undergoing Coronary Artery Bypass Graft Surgery: GLUCO-CABG Trial.

OBJECTIVE: The optimal level of glycemic control needed to improve outcomes in cardiac surgery patients remains controversial. RESEARCH DESIGN AND METHODS: We randomized patients with diabetes (n = 152) and without diabetes (n = 150) with hyperglycemia to an intensive glucose target of 100-140 mg/dL (n = 151) or to a conservative target of 141-180 mg/dL (n = 151) after coronary artery bypass surgery (CABG) surgery. After the intensive care unit (ICU), patients received a single treatment regimen in the hospital and 90 days postdischarge. Primary outcome was differences in a composite of complications, including mortality, wound infection, pneumonia, bacteremia, respiratory failure, acute kidney injury, and major cardiovascular events. RESULTS: Mean glucose in the ICU was 132 ± 14 mg/dL (interquartile range [IQR] 124-139) in the intensive and 154 ± 17 mg/dL (IQR 142-164) in the conservative group (P < 0.001). There were no significant differences in the composite of complications between intensive and conservative groups (42 vs. 52%, P = 0.08). We observed heterogeneity in treatment effect according to diabetes status, with no differences in complications among patients with diabetes treated with intensive or conservative regimens (49 vs. 48%, P = 0.87), but a significant lower rate of complications in patients without diabetes treated with intensive compared with conservative treatment regimen (34 vs. 55%, P = 0.008). CONCLUSIONS: Intensive insulin therapy to target glucose of 100 and 140 mg/dL in the ICU did not significantly reduce perioperative complications compared with target glucose of 141 and 180 mg/dL after CABG surgery. Subgroup analysis showed a lower number of complications in patients without diabetes, but not in patients with diabetes treated with the intensive regimen. Large prospective randomized studies are needed to confirm these findings.

Impairments in site-specific AS160 phosphorylation and effects of exercise training.

The purpose of this study was to determine if site-specific phosphorylation at the level of Akt substrate of 160 kDa (AS160) is altered in skeletal muscle from sedentary humans across a wide range of the adult life span (18-84 years of age) and if endurance- and/or strength-oriented exercise training could rescue decrements in insulin action and skeletal muscle AS160 phosphorylation. A euglycemic-hyperinsulinemic clamp and skeletal muscle biopsies were performed in 73 individuals encompassing a wide age range (18-84 years of age), and insulin-stimulated AS160 phosphorylation was determined. Decrements in whole-body insulin action were associated with impairments in insulin-induced phosphorylation of skeletal muscle AS160 on sites Ser-588, Thr-642, Ser-666, and phospho-Akt substrate, but not Ser-318 or Ser-751. Twelve weeks of endurance- or strength-oriented exercise training increased whole-body insulin action and reversed impairments in AS160 phosphorylation evident in insulin-resistant aged individuals. These findings suggest that a dampening of insulin-induced phosphorylation of AS160 on specific sites in skeletal muscle contributes to the insulin resistance evident in a sedentary aging population and that exercise training is an effective intervention for treating these impairments.

Prevalence, quality of care, and complications in long term care residents with diabetes: a multicenter observational study.

BACKGROUND: Few studies have reported on the quality of diabetes care and glycemic control adjusted for medication use in long term care (LTC) facilities. METHODS: This observational study analyzed diabetes prevalence and management and the impact of glycemic control on clinical outcome in elderly subjects admitted to 3 community LTC facilities. RESULTS: Among 1409 LTC residents (age 79.7 ± 12 years), the prevalence of diabetes was 34.2%. Subjects with diabetes were either on no pharmacological agents (10%) or were treated with sliding scale regular insulin (SSI, 25%), oral antidiabetic drugs (OAD, 5%), insulin (34%), or with combination of OAD and insulin (26%). Patients with diabetes had a mean daily BG of 156 ± 39 mg/dL and a mean admission HbA1c of 6.7% ± 1.1%. Compared with nondiabetes, residents with diabetes had higher number of complications (54% vs 45%, P < .001), infections (26% vs 21%, P = .036), emergency room (ER) and hospital transfers (37% vs 30%, P = .003), but similar mortality (15% vs 14%, P = .56). A total of 43% of residents with diabetes had a BG less than 70 mg/dL, and those with hypoglycemia had longer median length of stay (LOS, 52 vs 29 days, P < .001), more ER or hospital transfers (56% vs 69%, P = .005), and mortality (20% vs 10%, P = .002) compared with residents without hypoglycemia. CONCLUSION: Diabetes is common in LTC residents and is associated with higher resource utilization and complications. Hypoglycemia is common and is associated with increased need of emergency room visits and hospitalization and higher mortality. Our findings emphasize the need for randomized trials evaluating the impact of different approaches to glycemic management on clinical outcome in LTC residents with diabetes.

The impact of continuous subcutaneous insulin infusion and multiple daily injections of insulin on glucose variability in older adults with type 2 diabetes.

AIMS: To determine whether continuous subcutaneous insulin infusion (CSII) or multiple daily injections of insulin (MDI) are associated with improved glycemic variability. METHODS: Type 2 diabetic patients ≥60 years of age were randomized to 12 months of CSII (n=53) or MDI (n=54) therapy. Patients were asked to complete monthly eight-point self-monitored glucose profiles (n=78) and continuous glucose monitoring systems (CGMS) for up to 72 h at Months 0, 6, and 12 (n=77). Within-day mean glucose, standard deviation (SD), range, pre- and post-prandial glucose, M value, and mean amplitude of glycemic excursions (MAGE) were calculated from eight-point profiles. Mean glucose, SD, range, area under the curve (AUC) high (>180 mg/dl) and AUC-low (<70 mg/dl) were calculated from CGMS. Mixed model analyses of variance were used to examine the associations between treatment, time, and the study outcomes, adjusting for any effects of sex. RESULTS: With the use of the eight-point profiles, CSII and MDI groups did not differ with respect to mean glucose, mean pre-prandial and post-prandial glucose, SD, range, M value, or MAGE. With the CGMS data, there were no significant between-group differences in measures of mean glucose, range, SD, AUC-high, or AUC-low. In both treatment groups, all measures improved over time (P<.0001) except for AUC-low (P=.68) which did not change. There were treatment-by-time interactions when considering the CGMS range (P=.04) and AUC-high (P=.001), but no significant differences were found at individual time points. CONCLUSIONS: Glucose variability improved equally with CSII and MDI treatment in older patients with type 2 diabetes.

Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system.

OBJECTIVE: To report a case that substantiates the presence of hypoglycemia at the time of death of a young man with type 1 diabetes, who was found unresponsive in his undisturbed bed in the morning. METHODS: We describe a 23-year-old man with a history of type 1 diabetes treated with an insulin pump, who had recurrent severe hypoglycemia. In an effort to understand these episodes better and attempt to eliminate them, a retrospective (non-real-time) continuous subcutaneous glucose monitoring system (CGMS) was attached to the patient. He was found dead in his undisturbed bed 20 hours later. The insulin pump and CGMS were both downloaded for postmortem study. RESULTS: Postmortem download of the data in the CGMS demonstrated glucose levels below 30 mg/dL around the time of his death, with only a minimal counter-regulatory response. This finding corresponded to a postmortem vitreous humor glucose of 25 mg/dL. An autopsy showed no major anatomic abnormalities that could have contributed to his death. CONCLUSION: To our knowledge, this is the first documentation of hypoglycemia at the time of death in a patient with the "dead-in-bed" syndrome. This report should raise the awareness of physicians to the potentially lethal effects of hypoglycemia and provide justification for efforts directed at avoiding nocturnal hypoglycemia.

A comparison study of continuous insulin infusion protocols in the medical intensive care unit: computer-guided vs. standard column-based algorithms.

PURPOSE: To compare the safety and efficacy of continuous insulin infusion (CII) via a computer-guided and a standard paper form protocol in a medical intensive care unit (ICU). METHODS: Multicenter randomized trial of 153 ICU patients randomized to CII using the Glucommander (n = 77) or a standard paper protocol (n = 76). Both protocols used glulisine insulin and targeted blood glucose (BG) between 80 mg/dL and 120 mg/dL. RESULTS: The Glucommander resulted in a lower mean BG value (103 ± 8.8 mg/dL vs. 117 ± 16.5 mg/dL, P < 0.001) and in a shorter time to reach BG target (4.8 ± 2.8 vs.7.8 hours ± 9.1 hours, P < 0.01), and once at target resulted in a higher percentage of BG readings within target (71.0 ± 17.0% vs. 51.3 ± 19.7%, P < 0.001) than the standard protocol. Mean insulin infusion rate in the Glucommander was similar to the standard protocol (P = 0.12). The percentages of patients with ≥1 episode of BG <40 mg/dL and <60 mg/dL were 3.9% and 42.9% in the Glucommander and 5.6% and 31.9% in the standard, respectively [P = not significant (NS)]. Repeated measures analyses show that the probabilities of BG reading <40 mg/dL or <60 mg/dL were not significantly different between groups (P = 0.969, P = 0.084) after accounting for within-patient correlations with or without adjusting for time effect. There were no differences between groups in the length of hospital stay (P = 0.704), ICU stay (P = 0.145), or inhospital mortality (P = 0.561). CONCLUSION: Both treatment algorithms resulted in significant improvement in glycemic control in critically ill patients in the medical ICU. The computer-based algorithm resulted in tighter glycemic control without an increased risk of hypoglycemic events compared to the standard paper protocol.

Acute myocardial infarction attributable to adrenergic crises in a patient with pheochromocytoma and neurofibromatosis 1.

OBJECTIVE: To describe a rare case of acute myocardial infarction in a patient with neurofibromatosis 1 and pheochromocytoma and to review the literature on the coexistence of these 2 diseases, the causes of myocardial injury in patients with pheochromocytoma, and the utility of genetic testing and pheochromocytoma screening for those patients and their families. METHODS: We present a case report, including the detailed clinical, laboratory, and radiographic data, results of adrenal mass pathology, and results of coronary angiography. We also survey other relevant reports available in the literature. RESULTS: A 43-year-old woman with a history of long-standing hypertension, neurofibromatosis 1, headaches, sweating, and palpitations presented to the hospital with chest pain and shortness of breath. She was found to have an acute myocardial infarction and pulmonary edema, as well as a right adrenal mass. A pheochromocytoma was suspected, and phenoxybenzamine was added to her treatment regimen. Cardiac catheterization showed nonobstructive coronary disease. The levels of plasma catecholamine metabolites were extremely high. The patient underwent uncomplicated laparoscopic right adrenalectomy 2 weeks after this admission. Surgical pathology confirmed the diagnosis of pheochromocytoma. CONCLUSION: Adrenergic crisis attributable to pheochromocytoma can result in acute myocardial infarction even in the absence of obstructive coronary disease. Inclusion of pheochromocytoma in the differential diagnosis of hypertension in patients with neurofibromatosis is very important and helps avoid mistakes in the management of such patients.

Blood pressure control--effects on diabetic nephropathy progression: how low does blood pressure have to be?

Hypertension and diabetes are independent risk factors for both cardiovascular disease and renal complications. Coexistence of these comorbid conditions predisposes the patient to a much greater risk of progression to end-stage renal disease. Combined with the increased cardiovascular mortality, this has led to recent Joint National Committee-VI recommendations for the initiation of antihypertensive therapy for people with diabetes at a blood pressure of 130/85 mm Hg, a level lower than that recommended for the nondiabetic population. Results of a review of recently published investigations on the effects of blood pressure on diabetic nephropathy progression are presented in this article. This review finds evidence to support reducing the mean arterial blood pressure to levels below 95 mm Hg, a level that is even lower than the blood pressure of 130/80 mm Hg (mean arterial pressure of 97 mm Hg) recommended by the American Diabetes Association and National Kidney Foundation. The effect of blood pressure on renal disease progression is linear and appears to have no lower threshold for the benefits of blood pressure reduction on limiting nephropathy progression. The answer to the question of how low does blood pressure have to be to minimize the effects of blood pressure on diabetic nephropathy progression might be "the lower, the better."