Merri Pendergrass

Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle

The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance.

Nonhypoglycemic Effects of Thiazolidinediones

The thiazolidinediones are a new class of compounds for treatment of type 2 diabetes mellitus. The efficacy of these drugs in decreasing plasma glucose levels is well established (1-6). Troglitazone, a member of this class, became available for clinical use in the United States in 1997 but was withdrawn in March 2000 because of reports of severe hepatic injury. Rosiglitazone and pioglitazone became available in 1999 and are approved as monotherapy and in combination with other oral hypoglycemic agents; pioglitazone is also approved in combination with insulin. The glucose-lowering effects of the thiazolidinediones are mediated primarily by decreasing insulin resistance at the level of the muscle and thereby increasing glucose uptake. To a lesser extent, they decrease insulin resistance in the liver and thereby decrease hepatic glucose production (1). The mechanisms of action of the thiazolidinediones are still being investigated; however, some of their actions are mediated through binding and activation of the peroxisome proliferatoractivated receptor- (PPAR-), a nuclear receptor that has a regulatory role in differentiation of cells, particularly adipocytes (7). This receptor is also expressed in several other tissues, including vascular tissue (7). The thiazolidinediones also decrease plasma concentrations of free fatty acids and in doing so may indirectly improve insulin sensitivity (8). Thiazolidinediones may also activate other members of the PPAR family of receptors (such as PPAR- and PPAR-), which along with PPAR serve as gene transcription factors (9). These receptors are present in many tissues, and although their functions are still being elucidated, the data suggest that they have many important effects. Thus, the thiazolidinediones may affect many organ systems and disease processes (9). Substantial evidence indicates that insulin resistance, along with compensatory hyperinsulinemia, not only contributes to hyperglycemia in type 2 diabetes but also may play a pathophysiologic role in other metabolic abnormalities. These include high levels of plasma triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, hypertension, abnormal fibrinolysis, and coronary heart disease (10-13). This cluster of abnormalities is called the insulin resistance syndrome, syndrome X, or the metabolic syndrome (14). Since thiazolidinediones directly improve insulin resistance (2), it has been proposed that they may correct other abnormalities of the insulin resistance syndrome, as well as improve hyperglycemia. Thus, use of these agents to treat patients with type 2 diabetes may confer benefits beyond decreases in glucose level. Because of the effects of thiazolidinediones on hyperinsulinemia and insulin resistance, their vascular effect is a subject of considerable research interest (Table 1). Table 1. Effects of the Thiazolidinediones on Cardiovascular Risk Factors We discuss the nonhypoglycemic effects of the thiazolidinediones that have been described in the literature. We emphasize their potential to improve other components of the insulin resistance syndrome, such as dyslipidemia, hypertension, impaired fibrinolysis, and atherosclerosis. We discuss their effects in other insulin-resistant states, such as the polycystic ovary syndrome; examine their effects on body weight and composition; and draw attention to other potential effects currently being investigated. Much of the data presented relates to troglitazone (the most extensively studied thiazolidinedione) but may be relevant to the other thiazolidinediones. In vitro data support the possibility of a class effect, although proof from currently ongoing clinical trials (Freed M, SmithKline Beecham; Wishner W, Takeda Pharmaceuticals. Personal communication) is needed. Long-term clinical trials are also needed to determine whether such reduction in risk factors will prevent cardiovascular disease. Cardiovascular Effects Epidemiologic studies have demonstrated that hyperinsulinemia, a marker for insulin resistance, is an independent risk factor for cardiovascular disease (47). Correction of insulin resistance may be clinically important in type 2 diabetes and may decrease risk for cardiovascular disease. In the United Kingdom Prospective Diabetes Study, treatment with metformin (another drug that decreases hyperinsulinemia and insulin resistance) was shown to produce greater reduction in cardiovascular disease events and mortality than sulfonylureas and insulin (48). The latter drugs decreased blood glucose level to a similar degree as metformin but did not decrease plasma insulin concentrations. This effect may have been mediated through a decrease in insulin resistance, although other effects of metformin, such as improvement in lipid profile, improved fibrinolysis, and prevention of weight gain, may be important (48). Further clinical trials are needed to determine whether treatment of diabetes with agents that reduce insulin resistance (such as the thiazolidinediones and metformin) is superior to use of agents that stimulate insulin secretion (such as sulfonylureas). The National Institutes of Health recently initiated such a clinical trial (49). Cardiac Output and Left Ventricular Mass Initial studies of cardiac function with thiazolidinedione therapy were performed because of reported cardiac enlargement in animals treated with drugs of this class (3). Ghazzi and colleagues (3) investigated whether patients with type 2 diabetes treated with troglitazone, 800 mg/d (a dosage higher than that used in clinical practice), or glyburide experienced an increase in cardiac mass or functional impairment. Two-dimensional echocardiography and pulsed Doppler ultrasonography demonstrated that neither troglitazone nor glyburide changed left ventricular mass index significantly over 48 weeks. However, substantial increases in stroke volume index and cardiac index and a statistically significant decrease in diastolic pressure and estimated peripheral resistance were observed in troglitazone-treated patients but not glyburide-treated patients, who experienced no change (3). These findings are reassuring and contrast with those of animal studies. Similar studies of rosiglitazone and pioglitazone have also demonstrated no adverse effect on cardiac mass or function (4, 5, 50). Nevertheless, thiazolidinediones are currently contraindicated in patients with advanced heart failure because of their effect on plasma volume (43). Lipid Metabolism and Oxidation Insulin resistance and type 2 diabetes are associated with a characteristic pattern of lipid abnormalities, including an elevated plasma triglyceride level and a low plasma high-density lipoprotein (HDL) cholesterol level. Plasma levels of low-density lipoprotein (LDL) cholesterol do not differ from those in nondiabetic persons, but qualitative changes in LDL cholesterol, with an increase in small, dense LDL cholesterol, are common (15, 51-55). In several clinical trials, troglitazone therapy significantly lowered triglyceride levels (3, 16, 17) and increased HDL cholesterol levels in persons with type 2 diabetes (3, 16). A modest increase in LDL cholesterol level was observed, but the ratio of LDL cholesterol to HDL cholesterol and apolipoprotein B levels did not change. Data published to date indicate that all of the thiazolidinediones increase HDL cholesterol levels and that troglitazone and pioglitazone decrease triglyceride levels (3-5, 16-18). A recent small study (19) demonstrated a possible difference in the lipid-lowering effects of thiazolidinediones: Compared with rosiglitazone, pioglitazone seemed to produce a greater decrease in the triglyceride level and a lesser increase in the LDL cholesterol level. However, the study was neither randomized nor double-blind. Further studies on such possible differences are therefore needed. Similar changes in lipid levels have been observed in nondiabetic persons with insulin resistance. Like troglitazone, pioglitazone significantly reduced fasting serum levels of triglycerides and increased fasting levels of HDL cholesterol in 20 patients with type 2 diabetes (56). The effects of the thiazolidinediones on LDL cholesterol are more complex. Persons with insulin resistance or type 2 diabetes are more likely than nondiabetic persons to have small, dense, triglyceride-rich LDL cholesterol particles (51). These characteristics may make LDL cholesterol susceptible to oxidation. Oxidative modification confers atherogenic properties on LDL cholesterol particles; this may be a key initial event in the progression of atherosclerosis (15) and is a measurable risk factor (52-55). Evidence suggests that PPAR- may be an important regulator of foam-cell gene expression and that oxidized LDL cholesterol regulates macrophage gene expression through activation of PPAR- (57). Furthermore, PPAR- promotes uptake of oxidized LDL cholesterol by macrophages (58). Thus, an interaction between PPAR- and oxidized LDL cholesterol may be important in the development of atherosclerosis in diabetes. Thiazolidinediones have been shown to substantially increase levels of total cholesterol and LDL cholesterol (4, 5). However, the increase is predominantly in the larger buoyant particles of LDL cholesterol, which may be less atherogenic than small, dense LDL cholesterol particles. Levels of the latter have been shown to decrease with troglitazone therapy (20). These data were confirmed in other studies demonstrating that troglitazone increased the resistance of LDL cholesterol to oxidation (20-24). Whether these effects are produced by the other thiazolidinediones or were related to vitamin E moiety in the troglitazone molecule is unclear and warrants further study. Although the effects of the thiazolidinediones on LDL cholesterol oxidation are in theory appealing, their role in preventing cardiovascular events is unclear. Of note, vitamin E, which also has antioxidant and free radicalscavenging prope

Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin: A retrospective observational pharmacy claims analysis

OBJECTIVE Cases of acute pancreatitis have been reported in association with exenatide, sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether exenatide or sitagliptin increase the risk of acute pancreatitis. RESEARCH DESIGN AND METHODS A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox proportional hazard models were built to compare the risk of acute pancreatitis between diabetic and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication use. RESULTS Incidence of acute pancreatitis in the nondiabetic control group, diabetic control group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI 1.7–2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group (0.9 [0.6–1.5]) and sitagliptin versus diabetic control group (1.0 [0.7–1.3]). CONCLUSIONS Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk.

Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward.

OBJECTIVE Hypoglycemia is associated with adverse outcomes in mixed populations of patients in intensive care units. It is not known whether the same risks exist for diabetic patients who are less severely ill. In this study, we aimed to determine whether hypoglycemic episodes are associated with higher mortality in diabetic patients hospitalized in the general ward. RESEARCH DESIGN AND METHODS This retrospective cohort study analyzed 4,368 admissions of 2,582 patients with diabetes hospitalized in the general ward of a teaching hospital between January 2003 and August 2004. The associations between the number and severity of hypoglycemic (≤50 mg/dl) episodes and inpatient mortality, length of stay (LOS), and mortality within 1 year after discharge were evaluated. RESULTS Hypoglycemia was observed in 7.7% of admissions. In multivariable analysis, each additional day with hypoglycemia was associated with an increase of 85.3% in the odds of inpatient death (P = 0.009) and 65.8% (P = 0.0003) in the odds of death within 1 year from discharge. The odds of inpatient death also rose threefold for every 10 mg/dl decrease in the lowest blood glucose during hospitalization (P = 0.0058). LOS increased by 2.5 days for each day with hypoglycemia (P < 0.0001). CONCLUSIONS Hypoglycemia is common in diabetic patients hospitalized in the general ward. Patients with hypoglycemia have increased LOS and higher mortality both during and after admission. Measures should be undertaken to decrease the frequency of hypoglycemia in this high-risk patient population.

Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes

Aim: The objectives of the study were to determine whether thiazolidinedione (TZD) use is associated with an increased risk of fracture in men and women with type 2 diabetes mellitus and to compare the effects of pioglitazone and rosiglitazone.

Effects of a subcutaneous insulin protocol, clinical education, and computerized order set on the quality of inpatient management of hyperglycemia: Results of a clinical trial†‡

BACKGROUND Inpatient hyperglycemia is associated with poor patient outcomes. It is unknown how best to implement glycemic management strategies in the non-intensive care unit (ICU) setting. OBJECTIVE To determine the effects of a multifaceted quality improvement intervention on the management of medical inpatients with diabetes mellitus or hyperglycemia. DESIGN Before-after trial. SETTING Geographically localized general medical service staffed by physicians assistants (PAs) and hospitalists. PATIENTS Consecutively enrolled patients with type 2 diabetes or inpatient hyperglycemia. INTERVENTION A detailed subcutaneous insulin protocol, an admission order set built into the hospitals computerized order entry system, and case-based educational workshops and lectures to nurses, physicians, and PAs. MEASUREMENTS Mean percent of glucose readings per patient between 60 and 180 mg/dL; percent patient-days with hypoglycemia; insulin use patterns; and hospital length of stay. RESULTS The mean percent of readings per patient between 60 and 180 mg/dL was 59% prior to the intervention and 65% afterward (adjusted effect size 9.7%; 95% confidence interval [CI], 0.6%-18.8%). The percent of patient days with any hypoglycemia was 5.5% preintervention and 6.1% afterward (adjusted odds ratio 1.1; 95% CI, 0.6-2.1). Use of scheduled nutritional insulin increased from 40% to 75% (odds ratio 4.5; 95% CI, 2.0-9.9) and adjusted length of stay decreased by 25% (95% CI, 9%-44%). Daily insulin adjustment did not improve, nor did glucose control beyond hospital day 3. CONCLUSIONS This multifaceted intervention, which was easy to implement and required minimal resources, was associated with improvements in both insulin ordering practices and glycemic control among non-ICU medical patients.

Using Regular Expressions to Abstract Blood Pressure and Treatment Intensification Information from the Text of Physician Notes

This case study examined the utility of regular expressions to identify clinical data relevant to the epidemiology of treatment of hypertension. We designed a software tool that employed regular expressions to identify and extract instances of documented blood pressure values and anti-hypertensive treatment intensification from the text of physician notes. We determined sensitivity, specificity and precision of identification of blood pressure values and anti-hypertensive treatment intensification using a gold standard of manual abstraction of 600 notes by two independent reviewers. The software processed 370 Mb of text per hour, and identified elevated blood pressure documented in free text physician notes with sensitivity and specificity of 98%, and precision of 93.2%. Anti-hypertensive treatment intensification was identified with sensitivity 83.8%, specificity of 95.0%, and precision of 85.9%. Regular expressions can be an effective method for focused information extraction tasks related to high-priority disease areas such as hypertension.

Effect of Board Certification on Antihypertensive Treatment Intensification in Patients With Diabetes Mellitus

Background— Regular recertification is mandatory to maintain board certification status in all specialties. However, the evidence that physicians’ performance decreases with time since initial certification is limited. We therefore carried out a study to determine whether the frequency of antihypertensive treatment intensification for diabetic patients changes with time since their physicians’ last board certification. Methods and Results— In this retrospective cohort study, we analyzed treatment of 8127 hypertensive patients with diabetes mellitus treated by 301 internists at primary care practices affiliated with 2 large academic hospitals. Patient visits with documented blood pressure ≥130/85 mm Hg between January 1, 2000, and August 31, 2005, were studied. The association between the number of years since the physician’s last board certification and the probability of pharmacological antihypertensive treatment intensification at a given visit was analyzed. Frequency of treatment intensification decreased from 26.7% for physicians who were board certified the previous year to 6.9% for physicians who were board certified 31 years before the visit. Treatment intensification rate was 22.5% for physicians certified ≤10 years ago versus 16.9% for physicians last certified >10 years ago (P<0.0001). Multivariable analysis adjusted for patient and visit characteristics and physician age showed that for every decade since the physician’s last board certification, the probability of treatment intensification decreased by 21.3% (P=0.0097). Conclusion— Physician intensification of pharmacological therapy for blood pressure levels above the recommended treatment goals decreases with time since the last board certification. This finding supports the current policy of mandatory recertification.

EFFECTS OF A COMPUTERIZED ORDER SET ON THE INPATIENT MANAGEMENT OF HYPERGLYCEMIA: A CLUSTER-RANDOMIZED CONTROLLED TRIAL

OBJECTIVE To determine the effects of a computerized order set on the inpatient management of diabetes and hyperglycemia. METHODS We conducted a cluster-randomized controlled trial on the general medical service of an academic medical center staffed by residents and hospitalists. Consecutively enrolled patients with diabetes mellitus or inpatient hyperglycemia were randomized on the basis of their medical team to usual care (control group) or an admission order set built into the hospitals computer provider order entry (CPOE) system (intervention group). All teams received a detailed subcutaneous insulin protocol and case-based education. The primary outcome was the mean percent of glucose readings per patient between 60 and 180 mg/dL. RESULTS Between April 5 and June 22, 2006, we identified 179 eligible study subjects. The mean percent of glucose readings per patient between 60 and 180 mg/dL was 75% in the intervention group and 71% in the usual care group (adjusted relative risk, 1.36; 95% confidence interval, 1.03 to 1.80). In comparison with usual care, the intervention group also had a lower patient-day weighted mean glucose (148 mg/dL versus 158 mg/dL, P = .04), less use of sliding-scale insulin by itself (25% versus 58%, P = .01), and no significant difference in the rate of severe hypoglycemia (glucose <40 mg/dL; 0.5% versus 0.3% of patient-days, P = .58). CONCLUSION The use of an order set built into a hospitals CPOE system led to improvements in glycemic control and insulin ordering without causing a significant increase in hypoglycemia. Other institutions with CPOE should consider adopting similar order sets as part of a comprehensive inpatient glycemic management program.

Effects of exercise and insulin on insulin signaling proteins in human skeletal muscle.

Insulin and exercise independently increase glucose metabolism in muscle. Moreover, exercise training or a prior bout of exercise increases insulin-stimulated glucose uptake in resting skeletal muscle. The present study was undertaken to compare how physiological hyperinsulinemia and moderate intensity aerobic exercise affect the tyrosine phosphorylation state and activity of insulin signaling molecules in healthy, physically inactive volunteers. Subjects had biopsies of the vastus lateralis muscle before and immediately after 30 min of either hyperinsulinemia (euglycemic insulin clamp) or moderate-intensity exercise on a cycle ergometer (approximately 60% of VO2max). Insulin receptor and IRS-1 tyrosine phosphorylation, association of the p85 regulatory subunit of PI 3-kinase with IRS-1, IRS-1 associated PI 3-kinase activity, and glycogen synthase activity were determined in muscle biopsy specimens taken from healthy subjects before and after insulin or exercise. Physiological hyperinsulinemia increased the rate of glucose disposal from 11.4 +/- 1.5 to 25.6 +/- 6.7 micromol x kg(-1) x min(-1) (P < 0.01), insulin receptor and IRS-1 tyrosine phosphorylation (173 +/- 19% and 159 +/- 35% of basal values, respectively, P < 0.05), association of the p85 regulatory subunit of PI 3-kinase with IRS-1 (159 +/- 10%, P < 0.05), and glycogen synthase fractional velocity (136 +/- 11%, P < 0.01). Exercise also increased glucose disposal, from 10.4 +/- 0.5 to 15.6 +/- 1.7 micromol x kg(-1) x min(-1) (P < 0.01) and glycogen synthase fractional velocity (253 +/- 35% of basal, P < 0.01). The exercise-induced increase in glycogen synthase was greater than that due to insulin (P < 0.05). In contrast to insulin, exercise decreased tyrosine phosphorylation of the insulin receptor to 72 +/- 10% of basal values (P < 0.05 vs basal and P < 0.05 vs insulin) and had no effect on IRS-1 tyrosine phosphorylation, or association of p85 with IRS-1. The exercise-induced decreased insulin receptor tyrosine phosphorylation could explain the well-known effect of exercise to enhance the sensitivity of muscle to insulin.