Search

Background: Despite current preventive therapies, patients with transient ischemic attack (TIA) and ischemic stroke remain at high risk for recurrent brain disease and cardiovascular events. In an effort to develop new therapies, abnormal glucose tolerance has recently been proposed as an interventional target. Among persons not otherwise known to be diabetic, impaired glucose tolerance (IGT) and diabetic glucose tolerance (DGT) are each associated with an increased risk for incident vascular disease, vascular disease mortality, and all-cause mortality. We conducted this study to determine if IGT and DGT are sufficiently common among patients with TIA and ischemic stroke to warrant therapeutic trials of antihyperglycemic agents., Methods: Men and women older than 45 years were recruited from 3 hospitals in south central Connecticut. Eligibility criteria included a recent TIA or nondisabling ischemic stroke, no history of physician-diagnosed diabetes mellitus, and a fasting plasma glucose level less than 126 mg/dL (<7.0 mmol / L). After an overnight fast, subjects were admitted to a clinical research center for a standard 75-g oral glucose tolerance test. Impaired glucose tolerance was defined by a 2-hour plasma glucose value of 140 to 199 mg/dL (7.8-11.0 mmol / L) and DGT by a value of 200 mg/dL or greater (> or =11.1 mmol/L)., Results: Between June 2000 and August 2003, we enrolled 98 eligible patients. The average time from TIA or stroke to measurement of glucose tolerance was 105 days (range, 24-180 days) and the median age was 71 years. Twenty-seven subjects (28%) had IGT and 24 (24%) had diabetes. In a forward stepwise logistic regression model, only a fasting plasma glucose level of 110 mg/dL or greater (> or =6.1 mmol / L) and lower waist circumference were associated with an increased risk for IGT or DGT., Conclusions: Impaired glucose tolerance and DGT are present in most persons with a recent TIA or ischemic stroke who have no history of diabetes and a fasting plasma glucose level less than 126 mg/dL (<7.0 mmol / L). Our findings bring new urgency to the initiation of research to examine the effectiveness of antihyperglycemic therapies among patients with cerebrovascular disease and abnormal glucose tolerance.

Objective: Recent studies suggest that strict perioperative glycemic control improves clinical outcomes after cardiothoracic surgery. However, optimal methods and targets for controlling blood glucose (BG) levels in this setting have not been established. Currently published intensive insulin infusion protocols (IIPs) have important practical limitations, which may affect their utility. In this article, the authors present their experience with a safe, effective, nurse-driven IIP, which was implemented simultaneously in 2 cardiothoracic intensive care units (CTICUs)., Design: Prospective cohort study., Setting: Tertiary referral hospital and community teaching hospital., Participants: CTICU patients., Interventions: A standardized, intensive IIP was used for all patients admitted to both CTICUs. Hourly BG levels, relevant baseline variables, and clinical interventions were collected prospectively from the active hospital chart and CTICU nursing records., Measurements and Main Results: The IIP was used 137 times in 118 patients. The median time required to reach target BG levels (100-139 mg/dL) was 5 hours. Once BG levels decreased below 140 mg/dL, 58% of 2,242 subsequent hourly BG values fell within the narrow target range, 73% within a "clinically desirable" range of 80 to 139 mg/dL, and 94% within a "clinically acceptable" range of 80 to 199 mg/dL. Only 5 (0.2%) BG values were less than 60 mg/dL, with no associated adverse clinical events., Conclusions: The IIP safely and effectively improved glycemic control in 2 CTICUs, with minimal hypoglycemia. Based on prior studies showing the benefits of strict glycemic control, the implementation of this IIP should help to reduce morbidity and mortality in CTICU patients.

This article reviews normal and abnormal carbohydrate metabolism in pregnancy, with an emphasis on the challenges that are faced by those who care for the pregnant woman who has hyperglycemia. The growing problem of type 2 diabetes in pregnancy, the controversial use of oral antihyperglycemic agents for the treatment of gestational diabetes, and the long-term issue of diabetes prevention in those whose hyperglycemia resolves postpartum are also addressed.

Clinically recognized disorders of glucose metabolism include impaired fasting glucose, impaired glucose tolerance (both termed prediabetes), and diabetes mellitus. Type 2 diabetes mellitus affects 6% to 13% of adults in the United States. Among patients with recent stroke, 70% will have known diabetes, occult diabetes (detectable on an oral glucose tolerance test), or prediabetes. Type 2 diabetes mellitus is associated with a two- to six-fold increased risk for first or recurrent ischemic stroke. The mechanisms for the association are myriad and include the effects of hyperglycemia on vascular tissues and coagulation, and aberrations in blood pressure regulation, lipid metabolism, endothelial function, vascular inflammation, lipid metabolism, smooth muscle cell proliferation, and fibrinolysis. The most effective strategies to prevent stroke among people with diabetes include blood pressure control, antiplatelet therapy, and statin therapy. Tight glycemic control is recommended to prevent microvascular disease, but the effect on macrovascular disease, including stroke, has not been proven. Target blood pressure should be less than 130/80. Antiplatelet therapy may be accomplished with 81 to 325 mg of aspirin daily or 75 mg of clopidogrel daily. Statins should be given in dosages effective to reduce low-density lipoprotein cholesterol to less than 100 mg/dL. For glycemic control, first line therapy for most patients is metformin, starting at 500 mg daily. With time, most patients will need two or three oral medications from different classes and many eventually will require insulin therapy. Prevention of diabetes may be best accomplished by identifying those at risk and modifying diet, weight, and exercise habits. Screening for prediabetes and diabetes is appropriate for men and women older than 45 years and all individuals with vascular disease. Insulin resistance and impaired insulin secretion is the major underlying defect in type 2 diabetes mellitus. It also affects 50% of nondiabetic subjects with a recent ischemic stroke. Emerging evidence has linked insulin resistance to the pathophysiologic derangements in type 2 diabetes mellitus that accelerate atherosclerosis. Treatment of insulin resistance with weight loss, exercise, or medication can correct these derangements, and represents a promising approach to stroke prevention.

Objective: To report a case of newly recognized diabetes, manifested by hyperglycemic crisis, as the presenting feature of an extrahepatic cholangiocarcinoma in situ., Methods: We summarize the initial clinical manifestations and pertinent laboratory, radiologic, and pathologic findings in a patient with hyperglycemic emergency and a biliary carcinoma in situ. A review of the literature involving cholangiocarcinoma, pancreatic tumors, and diabetes mellitus is also presented., Results: An 85-year-old woman with no prior history of hyperglycemia presented to the hospital in hyperglycemic crisis, without identifiable precipitants. Further work-up disclosed a tumor in the common bile duct. Pathologic analysis, after pancreatoduodenectomy, demonstrated a carcinoma in situ without extension to nearby structures. Adjacent pancreatic islet cells appeared normal. Screening for all relevant islet cell autoantibodies was negative. After tumor removal, mild hyperglycemia persisted, although without insulin requirements., Conclusion: Extrahepatic cholangiocarcinoma and diabetes are not usually associated, and to our knowledge, this is the first reported case of a hyperglycemic emergency with this specific type of tumor. The cause-and-effect relationship between the patient's biliary carcinoma in situ and diabetes obviously cannot be confirmed; however, in the absence of other identifiable conditions, it is reasonable to speculate that some factor (or factors) produced by the tumor had a role in the metabolic decompensation. Such a relationship has been considered by others concerning the well-described association between diabetes and carcinoma of the pancreas, in which the underlying pathophysiologic process seems to be insulin resistance. This unusual case of secondary diabetes emphasizes the importance of considering the precise "cause" of the hyperglycemia when the presentation is atypical, as it was in this older, lean patient without risk factors for diabetes.

Microalbuminuria is a novel atherosclerotic risk factor in patients with type 2 diabetes mellitus (DM) and predicts future cardiovascular events. Endothelial dysfunction and systemic inflammation have been proposed as common links between microalbuminuria and cardiovascular disease. However, no study has assessed the relation between microalbuminuria and vascular dysfunction as measured by brachial artery reactivity (BAR) in DM. We evaluated 143 patients (85 men; mean age 60.0 +/- 6.7 years) with DM (mean duration 8.2 +/- 7.4 years) enrolled in the Detection of Ischemia in Asymptomatic Diabetics study. Subjects were categorized as those with microalbuminuria (ratio of urinary albumin to creatinine 30 to 299 microg/mg creatinine, n = 28) and those with normoalbuminuria (ratio of urinary albumin to creatinine 0 to 29.9 microg/mg creatinine, n = 115). High-resolution ultrasound BAR testing was used to measure endothelium-dependent and endothelium-independent vasodilations. C-reactive protein was measured as a marker of systemic inflammation. Patients with microalbuminuria and normoalbuminuria had similar baseline characteristics, with the exception that those with microalbuminuria had a longer duration of DM (p = 0.03). Endothelium-dependent vasodilation at 1 minute (p = 0.01) and endothelium-independent vasodilation at 3 minutes (p = 0.007) were significantly less in patients with microalbuminuria. In addition, 96% of patients with microalbuminuria and 76% of those with normoalbuminuria had impaired endothelium-dependent vasodilation (<8%, p = 0.01). Microalbuminuria was an independent predictor of endothelium-dependent vasodilation in the entire cohort (p = 0.045) and after excluding patients on hormone replacement therapy (p = 0.01). Levels of C-reactive protein were significantly higher in patients with microalbuminuria than in those with normoalbuminuria (p = 0.02). We conclude that in DM the presence of microalbuminuria is associated with impaired endothelium-dependent and endothelium-independent vasodilations of the brachial artery and a higher degree of systemic inflammation. In addition, microalbuminuria is an independent predictor of endothelial dysfunction in asymptomatic patients with DM, especially in the absence of hormone replacement therapy.

Objective: To assess the prevalence and clinical predictors of silent myocardial ischemia in asymptomatic patients with type 2 diabetes and to test the effectiveness of current American Diabetes Association screening guidelines., Research Design and Methods: In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 1,123 patients with type 2 diabetes, aged 50-75 years, with no known or suspected coronary artery disease, were randomly assigned to either stress testing and 5-year clinical follow-up or to follow-up only. The prevalence of ischemia in 522 patients randomized to stress testing was assessed by adenosine technetium-99m sestamibi single-photon emission-computed tomography myocardial perfusion imaging., Results: A total of 113 patients (22%) had silent ischemia, including 83 with regional myocardial perfusion abnormalities and 30 with normal perfusion but other abnormalities (i.e., adenosine-induced ST-segment depression, ventricular dilation, or rest ventricular dysfunction). Moderate or large perfusion defects were present in 33 patients. The strongest predictors for abnormal tests were abnormal Valsalva (odds ratio [OR] 5.6), male sex (2.5), and diabetes duration (5.2). Other traditional cardiac risk factors or inflammatory and prothrombotic markers were not predictive. Ischemic adenosine-induced ST-segment depression with normal perfusion (n = 21) was associated with women (OR 3.4). Selecting only patients who met American Diabetes Association guidelines would have failed to identify 41% of patients with silent ischemia., Conclusions: Silent myocardial ischemia occurs in greater than one in five asymptomatic patients with type 2 diabetes. Traditional and emerging cardiac risk factors were not associated with abnormal stress tests, although cardiac autonomic dysfunction was a strong predictor of ischemia.

Strict glycemic control improves clinical outcomes in critically ill patients. However, practical tools for frequent monitoring of blood glucose (BG) levels in the intensive care unit (ICU) are limited. The Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA) is currently approved for detecting glycemic excursions in outpatients with diabetes mellitus. The use of this device has never been carefully examined in the inpatient setting. This preliminary study was designed to investigate the accuracy of the CGMS in critically ill patients admitted to a medical ICU (MICU). Subjects at risk for hyperglycemia were recruited from among all patients admitted to our MICU. CGMS sensors were implanted for up to 72 h. Study subjects wore between one and five consecutive sensors. Four or more standard capillary BG readings were recorded per 24 h. All paired meter-sensor (M-S) readings were used both for CGMS calibration and for data analysis. Twenty-two MICU patients wore 41 CGMS sensors, yielding 546 M-S BG pairs. Overall, the Pearson correlation coefficient ( r ) was 0.88, with a mean M-S difference of 3.3 +/- 26.7 mg/dL (0.6 +/- 17.4%) and a mean absolute M-S difference of 19.7 +/- 18.3 mg/dL (12.8 +/- 11.9%). Clarke Error Grid analysis categorized 98.7% of the M-S pairs within "clinically acceptable" zones A and B. The CGMS is promising for potential use in critically ill patients. If validated in larger studies, the device could serve as a useful research tool for investigating the role of hyperglycemia (and strict glycemic control) in ICU patients. If further developed as a "real-time" glucose sensor, CGMS technology could ultimately prove clinically useful in the ICU, by decreasing nursing workload and/or by providing alarm signals for impending glycemic excursions.

Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.

Hypercalcemia is a common metabolic condition encountered in both inpatient and outpatient settings. Physicians can more successfully diagnose and treat patients when armed with a thorough understanding of normal calcium metabolism and how it can be disrupted by disease. In virtually all cases, the cause of an elevated serum calcium concentration can be quickly ascertained through the use of selected diagnostic tests. Effective treatment options can then be implemented.

Effective diagnostic and therapeutic strategies for patients with elevated serum calcium concentrations require a thorough understanding of normal calcium metabolism and how it may be disrupted by disease.

Objective: In a recent randomized controlled trial, lowering blood glucose levels to 80-110 mg/dl improved clinical outcomes in critically ill patients. In that study, the insulin infusion protocol (IIP) used to normalize blood glucose levels provided valuable guidelines for adjusting insulin therapy. In our hands, however, ongoing expert supervision was required to effectively manage the insulin infusions. This work describes our early experience with a safe, effective, nurse-implemented IIP that provides detailed insulin dosing instructions and requires minimal physician input., Research Design and Methods: We collected data from 52 medical intensive care unit (MICU) patients who were placed on the IIP. Blood glucose levels were the primary outcome measurement. Relevant clinical variables and insulin requirements were also recorded. MICU nurses were surveyed regarding their experience with the IIP., Results: To date, our IIP has been employed 69 times in 52 patients admitted to an MICU. Using the IIP, the median time to reach target blood glucose levels (100-139 mg/dl) was 9 h. Once blood glucose levels fell below 140 mg/dl, 52% of 5,808 subsequent hourly blood glucose values fell within our narrow target range; 66% within a "clinically desirable" range of 80-139 mg/dl; and 93% within a "clinically acceptable" range of 80-199 mg/dl. Only 20 (0.3%) blood glucose values were <60 mg/dl, none of which resulted in clinically significant adverse events. In general, the IIP was readily accepted by our MICU nursing staff, most of whom rated the protocol as both clinically effective and easy to use., Conclusions: Our nurse-implemented IIP is safe and effective in improving glycemic control in critically ill patients.

Endocrine emergencies are commonly encountered in the ICU. This article focuses on several important endocrine emergencies, including diabetic hyperglycemic states, adrenal insufficiency, myxedema coma, thyroid storm, and pituitary apoplexy. Other endocrine issues that are related to intensive care, such as intensive insulin therapy, relative adrenal insufficiency, and thyroid function test abnormalities are also covered in detail.

Context: According to package inserts, metformin is contraindicated in diabetic patients receiving drug treatment for heart failure therapy, and thiazolidinediones are not recommended in diabetic patients with symptoms of advanced heart failure. Little is known about patterns of use of these antihyperglycemic drugs in diabetic patients with heart failure., Objective: To determine the proportions of patients hospitalized with heart failure and concomitant diabetes treated with metformin or thiazolidinediones., Design: Serial cross-sectional measurements using data from retrospective medical record abstraction., Setting: Nongovernmental acute care hospitals in the United States., Patients: Two nationally representative samples of Medicare beneficiaries hospitalized with the primary diagnosis of heart failure and concomitant diabetes between April 1998 and March 1999 and between July 2000 and June 2001., Main Outcome Measures: The prescription of either metformin or a thiazolidinedione at hospital discharge., Results: In the 1998-1999 sample (n = 12 505), 7.1% of patients were discharged with a prescription for metformin, 7.2% with a prescription for a thiazolidinedione, and 13.5% with a prescription for either drug. In the 2000-2001 sample (n = 13 158), metformin use increased to 11.2%, thiazolidinedione use to 16.1%, and use of either drug to 24.4% (P<.001 for all comparisons). Similar increases were seen among patients of all age groups, all races, and both sexes., Conclusions: The use of metformin and thiazolidinediones is common and has increased rapidly in Medicare beneficiaries with diabetes and heart failure in direct contrast with explicit warnings against this practice by the Food and Drug Administration. Further studies to establish the safety and effectiveness of this practice are needed to ensure optimal care of patients with diabetes and heart failure.

Background and Purpose: The aim of this study was to determine the effectiveness of pioglitazone compared with placebo for improving insulin sensitivity among nondiabetic patients with a recent transient ischemic attack (TIA) or nondisabling ischemic stroke and impaired insulin sensitivity., Methods: Eligible subjects were men and women >45 years of age who had no history of diabetes, fasting glucose <7.0 mmol/L, and impaired insulin sensitivity according to an index calculated from insulin and glucose blood levels obtained during an oral glucose tolerance test. Eligible subjects were randomized to pioglitazone 45 mg/d or placebo. After 3 months of therapy, the glucose tolerance test was repeated., Results: Between July 2000 and June 2001, we performed oral glucose tolerance tests on 75 patients with no history of diabetes, among whom 36 (50%) were found to have impaired insulin sensitivity and fasting glucose <7.0 mmol/L. Among these 36, 20 consented to the trial. Patients assigned to pioglitazone (n=10) and placebo (n=10) were similar in insulin sensitivity, age, obesity, and index event (stroke compared with TIA), but patients assigned to pioglitazone were less likely to be male (4 compared with 9). The mean proportional increase in insulin sensitivity was 62% among patients assigned to pioglitazone compared with a -1% decline among patients assigned to placebo (P=0.0006). Mean C-reactive protein concentration declined from 0.30 to 0.20 mg/L among patients assigned to pioglitazone and increased from 0.41 to 0.45 mg/L among patients assigned to placebo (P=0.06 for comparison of mean change)., Conclusions: Pioglitazone is effective for improving insulin sensitivity among patients with recent TIA or stroke and impaired insulin sensitivity.

Objectives: To determine the prevalence of impaired insulin sensitivity among nondiabetic patients with a recent TIA or nondisabling ischemic stroke., Methods: Eligible subjects were nondiabetic men and women over age 45 years who were hospitalized with a TIA or ischemic stroke. To measure insulin sensitivity, subjects underwent an oral glucose tolerance test between 2 and 6 months after their event. Impaired insulin sensitivity was defined by a value of < or =2.5 on the Composite Insulin Sensitivity Index derived from insulin and glucose values during the test., Results: Between July 2000 and June 2001, we identified 177 eligible patients, among whom 105 declined to participate and 72 enrolled. The median age of participants was 71 years and 46 (64%) were men. The baseline event was stroke for 57 subjects (79%). A history of myocardial infarction (MI) was reported by 14 subjects (19%), and 16 (22%) were obese (body mass index > 30). Fasting glucose was normal (<110 mg/dL) for 58 (80%) participants and impaired (110 to 125 mg/dL) for 14 (20%). Among 72 participants, the median insulin sensitivity index value was 2.6 (range 0.9 to 10.2). The prevalence of impaired insulin sensitivity was 36 of 72 (50%, 95% CI 38% to 62%). Impaired insulin sensitivity was more prevalent among younger patients and patients with obesity, lacunar stroke etiology, and disability (Rankin grade >1)., Conclusion: Impaired insulin sensitivity is highly prevalent among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. This finding has important therapeutic implications if treatment to improve insulin sensitivity is shown to reduce risk for subsequent stroke and heart disease.

Metformin, a biguanide, has been available in the US for the treatment of type 2 diabetes mellitus for nearly 8 years. Over this period of time, it has become the most widely prescribed antihyperglycaemic agent. Its mechanism of action involves the suppression of endogenous glucose production, primarily by the liver. Whether the drug actually has an insulin sensitising effect in peripheral tissues, such as muscle and fat, remains somewhat controversial. Nonetheless, because insulin levels decline with metformin use, it has been termed an 'insulin sensitiser'. Metformin has also been shown to have several beneficial effects on cardiovascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular outcomes in patients with diabetes. Cardiovascular disease, impaired glucose tolerance and the polycystic ovary syndrome are now recognised as complications of the insulin resistance syndrome, and there is growing interest in the management of this extraordinarily common metabolic disorder. While diet and exercise remain the cornerstone of therapy for insulin resistance, pharmacological intervention is becoming an increasingly viable option. We review the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits it provides over and above its effect on glucose levels alone. We also discuss its potential role for a variety of insulin resistant and prediabetic states, including impaired glucose tolerance, obesity, polycystic ovary syndrome and the metabolic abnormalities associated with HIV disease.

Background and Purpose: Resistance to insulin-mediated glucose uptake by peripheral tissues is a cardinal defect in type 2 diabetes mellitus. Insulin resistance is also common among nondiabetic individuals, and may be an important risk factor for stroke in both populations. The authors review the definition, epidemiology, and treatment of insulin resistance., Methods: The authors searched Medline (1977-2001) and reviewed bibliographies to identify pertinent English-language publications., Results: Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. The principal pathophysiologic defect is impaired intracellular signaling in muscle tissue leading to defective glycogen synthesis. Insulin resistance is associated with numerous metabolic, hematologic, and cellular events that promote atherosclerosis and coagulation. The association between insulin resistance and risk for stroke has been examined in four case-control studies and five prospective observational cohort studies. Six of the nine studies are methodologically sound and provide evidence that insulin resistance is associated with risk for stroke., Conclusion: Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.

There is now widespread appreciation of the importance of maintaining glucose levels as close to the normal range as possible among outpatients with diabetes. However, the importance of tight glucose control in inpatients is less well established. During the past several years, it has become apparent that hyperglycemia in hospitalized patients, especially those in the postoperative setting, is associated with poorer outcomes. In addition, two randomized trials have shown improved outcomes with intensive glucose management in acutely ill patients. Based on these studies and our own experience, we propose guidelines and a framework for improving the glycemic control of hospitalized patients.

We examined the effect of three months of rosiglitazone treatment (4 mg b.i.d.) on whole-body insulin sensitivity and in vivo peripheral adipocyte insulin sensitivity as assessed by glycerol release in microdialysis from subcutaneous fat during a two-step (20 and 120 mU.m(-2).min(-1)) hyperinsulinemic-euglycemic clamp in nine type 2 diabetic subjects. In addition, the effects of rosiglitazone on liver and muscle triglyceride content were assessed by (1)H-nuclear magnetic resonance spectroscopy. Rosiglitazone treatment resulted in a 68% (P < 0.002) and a 20% (P < 0.016) improvement in insulin-stimulated glucose metabolism during the low- and high- dosage-insulin clamps, respectively, which was associated with approximately 40% reductions in plasma fatty acid concentration (P < 0.05) and hepatic triglyceride content (P < 0.05). These changes were associated with a 39% increase in extramyocellular lipid content (P < 0.05) and a 52% increase in the sensitivity of peripheral adipocytes to the inhibitory effects of insulin on lipolysis (P = 0.04). In conclusion, these results support the hypothesis that thiazolidinediones enhance insulin sensitivity in patients with type 2 diabetes by promoting increased insulin sensitivity in peripheral adipocytes, which results in lower plasma fatty acid concentrations and a redistribution of intracellular lipid from insulin responsive organs into peripheral adipocytes.

The dramatic increase in the number of classes of oral antidiabetic agents has provided physicians with more tools to help patients manage type 2 diabetes. Of course, glycemic control must remain paramount when choosing an oral agent. However, the mechanism of action of an agent, its side effect profile, and the potential for various nonglycemic benefits may help determine which is the best drug for an individual patient.

Context: Care of patients with type 2 diabetes has been revolutionized throughout the past several years-first, by the realization of the importance of tight glycemic control in forestalling complications, and second, by the availability of several unique classes of oral antidiabetic agents. Deciphering which agent to use in certain clinical situations is a new dilemma facing the primary care physician., Objective: To systematically review available data from the literature regarding the efficacy of oral antidiabetic agents, both as monotherapy and in combination., Data Sources: A MEDLINE search was performed to identify all English-language reports of unique, randomized controlled clinical trials involving recently available oral agents for type 2 diabetes. Bibliographies were also reviewed to find additional reports not otherwise identified., Study Selection and Data Extraction: Studies (63) were included in the analysis if they had a study period of at least 3 months; if each group contained at least 10 subjects at the study's conclusion; and if hemoglobin A(1c) was reported. When multiple dosages of a drug were tested, the results of the highest approved dosage were used. In placebo-controlled trials, hemoglobin A(1c) data are presented as the difference between the change in treated vs placebo subjects., Data Synthesis: Five distinct oral drug classes are now available for the treatment of type 2 diabetes. Compared with placebo treatment, most of these agents lower hemoglobin A(1c) levels approximately 1% to 2%. Equivalent efficacy is usually demonstrated when different agents are compared with one another in the same study population. When they are used in combination, there are additional glycemic benefits. Long-term vascular risk reduction has been demonstrated only with sulfonylureas and metformin., Conclusions: With few exceptions, the available oral antidiabetic agents are equally effective at lowering glucose concentrations. Their mechanisms of action are different, however, and as a result they appear to have distinct metabolic effects. These are reflected in their adverse effect profiles and their effect on cardiovascular risk, which may influence drug choice.

The aim of the study was to determine the frequency of undiagnosed abnormal glucose metabolism in patients with idiopathic sensory neuropathy. Patients were separated into two groups depending on presence or absence of painful symptoms, and an oral glucose tolerance test was performed. Of the 48 patients studied, those with painful symptoms had a higher frequency of abnormal glucose metabolism than literature-based controls, whereas patients without painful symptoms showed no difference. Comparison of patients with and without painful symptoms had a P-value of 0.02. The results indicate the need to consider undiagnosed abnormal glucose metabolism in patients with idiopathic sensory neuropathy., (Copyright 2001 John Wiley & Sons, Inc.)

To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.

Objective: To describe the first patient with a neuroendocrine tumor secreting serotonin, insulin, and glucagon and having the corresponding clinical syndromes., Methods: We present a detailed case report, including serial laboratory and clinical findings, in a man with type 2 diabetes, symptomatic hypoglycemia, and the carcinoid syndrome and in whom a plurihormonal metastatic neuroendocrine neoplasm was ultimately diagnosed., Results: In a 58-year-old man with type 2 diabetes, which was treated effectively with a sulfonylurea for 7 years, episodes of hypoglycemia developed. After discontinuation of the orally administered agent, the hypoglycemic episodes initially resolved but then recurred and were associated with inappropriately increased plasma insulin concentrations. In addition, the patient had symptoms and biochemical evidence of the carcinoid syndrome. Computed tomography of the abdomen showed multiple hypodense lesions in the liver, and ultrasound-guided fine-needle aspiration of a liver mass was performed. Undifferentiated neuroendocrine tumor with hepatic metastatic involvement was diagnosed. After a hepatic artery embolization procedure, the hypoglycemia was alleviated, but hyperglycemia soon recurred, associated with inappropriately increased serum glucagon concentrations. The patient's course strongly suggested the presence of a plurihormonal tumor secreting serotonin, insulin, and glucagon., Conclusion: To our knowledge, this is the first reported case of a patient with a neuroendocrine neoplasm secreting serotonin, glucagon, and insulin, manifested by the carcinoid syndrome, hyperglycemia, and hypoglycemia.

We describe a case of pulmonary hypertension, initially thought to be idiopathic, which resolved after treatment of Graves' hyperthyroidism. Results of pulmonary artery catheterization before and after treatment are reported, and the effects of thyrotoxicosis on hemodynamics and pulmonary function are briefly reviewed. Possible mechanisms for development of pulmonary hypertension caused by hyperthyroidism include pulmonary vascular endothelial dysfunction or damage because of autoimmunity or the high cardiac output state, or increased metabolism of intrinsic pulmonary vasodilators.

Many malignancies may present with metastases to the pituitary gland. The association of thyroid carcinoma with pituitary metastases is, however, very rare. This report describes two patients in whom metastases from a papillary thyroid carcinoma to the pituitary gland resulted in panhypopituitarism with blunted endogenous thyrotropin (TSH) production following withdrawal of levothyroxine. Both required the use of recombinant human TSH prior to radioiodine therapy. Symptoms of hypopituitarism may be difficult to distinguish clinically from those of hypothyroidism in the setting of levothyroxine withdrawal. Clinicians should be aware of the clinical and biochemical manifestations of this rare association.

A 26-year old woman presented with a thyroid nodule. Ultrasound and scintigraphy confirmed the presence of a 3.5-cm non-functioning mass in the left lobe. A fine needle aspiration demonstrated unusual, malignant-appearing cells, and thyroidectomy was performed. At gross pathological sectioning, the lesion was clearly attached to, but not part of, the thyroid. Microscopic features indicated an atypical carcinoid arising in a cervical remnant of the thymus. This appears to be the first case of ectopic thymic carcinoid presenting as a thyroid nodule.

Background: Combination therapy is logical for patients with non-insulin-dependent (type 2) diabetes mellitus, because they often have poor responses to single-drug therapy. We studied the efficacy and physiologic effects of metformin and troglitazone alone and in combination in patients with type 2 diabetes., Methods: We randomly assigned 29 patients to receive either metformin or troglitazone for three months, after which they were given both drugs for another three months. Plasma glucose concentrations during fasting and postprandially and glycosylated hemoglobin values were measured periodically during both treatments. Endogenous glucose production and peripheral glucose disposal were measured at base line and after three and six months., Results: During metformin therapy, fasting and postprandial plasma glucose concentrations decreased by 20 percent (58 mg per deciliter [3.2 mmol per liter], P<0.001) and 25 percent (87 mg per deciliter [4.8 mmol per liter], P<0.001), respectively. The corresponding decreases during troglitazone therapy were 20 percent (54 mg per deciliter [2.9 mmol per liter], P=0.01) and 25 percent (83 mg per deciliter [4.6 mmol per liter], P<0.001). Endogenous glucose production decreased during metformin therapy by a mean of 19 percent (P=0.001), whereas it was unchanged by troglitazone therapy (P=0.04 for the comparison between groups). The mean rate of glucose disposal increased by 54 percent during troglitazone therapy (P=0.006) and 13 percent during metformin therapy (P= 0.03 for the comparison within the group and between groups). In combination, metformin and troglitazone further lowered fasting and postprandial plasma glucose concentrations by 18 percent (41 mg per deciliter [2.3 mmol per liter], P=0.001) and 21 percent (54 mg per deciliter [3.0 mmol per liter], P<0.001), respectively, and the mean glycosylated hemoglobin value decreased 1.2 percentage points., Conclusions: Metformin and troglitazone have equal and additive beneficial effects on glycemic control in patients with type 2 diabetes. Metformin acts primarily by decreasing endogenous glucose production, and troglitazone by increasing the rate of peripheral glucose disposal.

Adults with hypopituitarism and documented growth hormone deficiency are now eligible for replacement therapy. What are the guidelines for diagnosis and treatment? More broadly, what are the implications for other adults with hyposomatotropism-namely, the elderly? And is there a therapeutic role for the hormone in patients with disease states such as osteoporosis, heart failure, and acute catabolic illness?

Humoral hypercalcemia of malignancy (HHM) results from the production of PTH-related protein (PTHrP) by human tumors. One previous study has reported the results of human (h) PTHrP(1-34) infusion into humans. In that report, hPTHrP(1-34) was found to be qualitatively similar to but 3- to 10-fold less potent than hPTH(1-34). Because hPTHrP(1-36) and not hPTH(1-34) is likely to be the actual amino-terminal secretory form of PTHrP, and because this previously reported lack of potency was unexpected, we repeated these studies using hPTHrP(1-36) and compared the results with those obtained with hPTH(1-34). Healthy subjects (n = 30) were infused over 6 h with either vehicle alone, hPTH(1-34) at a dose of 8 pmol/kg.h, or hPTHrP(1-36) at doses of 8 or 80 pmol/kg.h. Both hPTH(1-34) and hPTHrP(1-36) caused an increase in serum ionized calcium, a decrease in serum phosphorus, an increase in the fractional excretion of phosphorus, a decrease in the tubular maximum for phosphorus, an increase in nephrogenous cAMP excretion, and suppression of endogenous PTH(1-84). Unlike events observed in HHM, hPTHrP(1-36) induced an increase in plasma 1,25-dihydroxyvitamin D2. In addition, fractional excretion of calcium was reduced by both hPTH(1-34) and hPTHrP(1-36). In their actions on serum calcium, renal calcium and phosphorus handling, and nephrogenous cAMP excretion, hPTHrP(1-36) and hPTH(1-34) appeared equivalent in potency. These studies indicate that short-term infusion of hPTHrP(1-36) into humans reproduces most but not all of the features of HHM. In contrast to the reported findings with hPTHrP(1-34), we found the potency of hPTHrP(1-36) to be comparable with that of hPTH(1-34) in vivo in humans. In addition, unlike the situation in HHM, hPTHrP(1-36) produces an increment in plasma 1,25-dihydroxyvitamin D2. Finally, hPTHrP(1-36) has been shown for the first time to have anticalciuric effects in humans. This would suggest that, in addition to osteoclastic bone resorption, tubular reabsorbtion of calcium by hPTHrP may contribute to the hypercalcemia in patients with HHM.

GH has considerable importance in the normal development and growth of bone. An additional role in the maintenance of the adult skeleton is suggested by the alterations in bone mineral density observed in states of deficient or excess GH secretion and in the bone formation response to GH replacement in GHD patients. Deficiency in the secretion of GH is also observed, with increasing and striking frequency after middle-age despite the lack of any defined pituitary disease or injury. Although a causal relationship between hyposomatotropism and osteopenia in normal elderly patients is hypothetical, intriguing therapeutic questions are raised. Preliminary trials of hGH in osteoporosis have not resulted in increases in BMD, but such studies suffer from methodological limitations, chief of which is the failure to account for the GH/IGF-I status of their subjects. Osteopenic patients with the lowest IGF-I levels may need to be assessed independently. The utility of hGH may be in preventing the senile component of osteoporosis, which appears to result mainly from defective bone formation. Such studies will require appropriate patient selection, longer treatment periods, and more sensitive measures of bone density. Combination and/or coherence therapy with other agents, particularly those that attenuate bone resorption, may also prove useful.