Shortfalls of the use of HbA1C-derived eAG in older adults with diabetes.

AIMS: The hemoglobin HbA1C (HbA1C) value, translated into estimated average glucose concentration (eAG), is commonly used to assess glycaemic control and manage treatment regimens in people with diabetes. However, the relationships among HbA1C-derived eAG, and mean glucose concentration derived from continuous glucose monitoring (CGM) in different populations have not been well studied. We examined this relationship in older people with diabetes and compared the results to those currently used in clinical practice. METHODS: Data from three studies evaluating CGM in older adults (≥70 years of age), with stable glycaemic control were analyzed retrospectively. Mean glucose and mean amplitude of glucose excursion (MAGE) were calculated from CGM data and correlated with HbA1C and HbA1C-derived eAG using the ADAG study formula. RESULTS: HbA1C and CGM data were analyzed from 90 patients with mean age 76±5 years, HbA1C 7.9±1.2% (63±13 mmol/mol) and 77% with Type 2 diabetes. The HbA1C and HbA1C-derived eAG correlated significantly with CGM-measured mean glucose (r(2)=0.30, p<0.0001) and MAGE (r(2)=0.16, p=0.00013) in this population and all its subgroups, but the slopes of the relationship between HbA1C and eAG or CGM-measured mean glucose were significantly different. CONCLUSIONS: HbA1C-derived eAG values may not accurately reflect CGM-measured mean glucose or MAGE in older adults with diabetes. Wide glucose excursions should be considered and HbA1C should be interpreted cautiously when making treatment changes based on HbA1C.

Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility.

BACKGROUND: Particulate air pollution has been associated with several adverse cardiovascular health outcomes, and people with diabetes may be especially vulnerable. One potential pathway is inflammation and endothelial dysfunction-processes in which cell adhesion molecules and inflammatory markers play important roles. AIM: To examine whether plasma levels of soluble intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) were associated with particle exposure in 92 Boston area residents with type 2 diabetes. METHODS: Daily average ambient levels of air pollution (fine particles (PM2.5), black carbon (BC) and sulphates) were measured approximately 500 m from the patient examination site and evaluated for associations with ICAM-1, VCAM-1 and vWF. Linear regressions were fit to plasma levels of ICAM-1, VCAM-1 and vWF, with the particulate pollutant index, apparent temperature, season, age, race, sex, glycosylated haemoglobin, cholesterol, smoking history and body mass index as predictors. RESULTS: Air pollutant exposure measures showed consistently positive point estimates of association with the inflammatory markers. Among participants not taking statins and those with a history of smoking, associations between PM(2.5), BC and VCAM-1 were particularly strong. CONCLUSIONS: These results corroborate evidence suggesting that inflammatory mechanisms may explain the increased risk of air pollution-associated cardiovascular events among those with diabetes.

What does postprandial hyperglycaemia mean?

AIMS: The potential importance of postprandial glucose (PPG) control in the development of complications in Type 2 diabetes is much debated. The recent American Diabetes Association (ADA) consensus statement discussed the role of postprandial hyperglycaemia in the pathogenesis of diabetic complications and concluded that the relationship between PPG excursions and the well-established risk factors for cardiovascular disease (CVD) should be further examined. Using the ADA statement as a starting point and including the more recent American College of Endocrinology guidelines on glycaemic control, a panel of experts in diabetes met to review the role of PPG within the context of the overall metabolic syndrome, in the development of complications in Type 2 diabetes. RESULTS: Post-prandial hyperglycaemia is a risk indicator for micro- and macrovascular complications, not only in patients with Type 2 diabetes but also in those with impaired glucose tolerance. In addition, the metabolic syndrome confers an increased risk of CVD morbidity and mortality. The debate focused on the relative contributions of postprandial hyperglycaemia, the metabolic syndrome and, in particular, raised triglyceride levels in the postprandial state, to the development of cardiovascular complications of diabetes. CONCLUSIONS: The panel recommended that in the prevention and management of microvascular complications of Type 2 diabetes, targeting both chronic and acute glucose fluctuations is necessary. Lowering the macrovascular risk also requires control of (postprandial) triglyceride levels and other components of the metabolic syndrome.

Diet and exercise in type 2 diabetes mellitus.

The question is no longer whether diet and exercise can benefit the individual with type 2 diabetes. Rather, the type and duration of exercise the magnitude of the effects on glycemic control, insulin sensitivity, and on risk factors for cardiovascular disease must be considered in determining the feasibility and acceptability of an intervention program. It is now clear that regular physical exercise is important in both the prevention and treatment of type 2 diabetes. The benefits of exercise are many and include increased energy expenditure, which, combined with dietary restriction, leads to decreased body fat, increased insulin sensitivity, improved long-term glycemic control, improved lipid profiles, lower blood pressure, and increased cardiovascular fitness. Persons with type 2 diabetes often find it difficult to exercise and are at increased risk for injury or exacerbation of underlying diseases or diabetic complications. Therefore, before starting an exercise program, all patients with type 2 diabetes should have a complete history and physical examination, with particular attention to evaluation of cardiovascular disease, medications that may affect glycemic control during or after exercise, and diabetic complications including retinopathy, nephropathy, and neuropathy. Exercise programs should be designed to start slowly, build up gradually, and emphasize moderately intense exercise performed at least three times a week and preferably five to seven times a week for best results.

Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy.

OBJECTIVE: To examine the contribution of nerve-axon reflex-related vasodilation to total acetylcholine-induced vasodilation in the skin of normal and diabetic subjects. RESEARCH DESIGN AND METHODS: The skin microcirculation was evaluated at the forearm level in 69 healthy subjects and 42 nonneuropathic diabetic patients and at the foot level in 27 healthy subjects and 101 diabetic patients (33 with neuropathy, 23 with Charcot arthropathy, 32 with peripheral vascular disease and neuropathy, and 13 without complications). Two single-point laser probes were used to measure total and neurovascular vasodilation response to the iontophoresis of 1% acetylcholine, 1% sodium nitroprusside, and deionized water. RESULTS: The neurovascular response to acetylcholine was significantly higher than the response to sodium nitroprusside and deionized water (P < 0.01). At the forearm level, the contribution of neurovascular response to the total response to acetylcholine was 35% in diabetic patients and 31% in control subjects. At the foot level, the contribution was 29% in diabetic patients without neuropathy and 36% in control subjects, while it was significantly diminished in the three neuropathic groups. A significantly lower nonspecific nerve-axon-related vasodilation was observed during the iontophoresis of sodium nitroprusside, which does not specifically stimulate the C nociceptive fibers. CONCLUSIONS: Neurovascular vasodilation accounts for approximately one-third of the total acetylcholine-induced vasodilation at both the forearm and foot levels. The presence of diabetic neuropathy results in reduction of both the total vasodilatory response to acetylcholine and the percentage contribution of neurovascular vasodilation to the total response. Acetylcholine and sodium nitroprusside cause vasodilation in the skin microcirculation through different pathways.

Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes.

OBJECTIVE: To evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients inadequately controlled by diet, focusing on changes in HbA1c, fasting plasma glucose (FPG), and mealtime glucose excursions. RESEARCH DESIGN AND METHODS: In this randomized double-blind study, patients with an HbA1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). HbA1c and FPG were evaluated regularly, and plasma glucose levels were determined after Sustacal challenge at weeks 0, 12, and 24. Hypoglycemia and other adverse events were recorded. RESULTS: At study end point, HbA1c was reduced from baseline with nateglinide and metformin but was increased with placebo (-0.5, -0.8, and +0.5%, respectively; P < or = 0.0001). Changes in FPG followed the same pattern (-0.7, -1.6, and +0.4 mmol/l; P < or = 0.0001). Combination therapy was additive (HbA1c -1.4% and FPG -2.4 mmol/l; P < or = 0.01 vs. monotherapy). After Sustacal challenge, there was a greater reduction in mealtime glucose with nateglinide monotherapy compared with metformin monotherapy or placebo (adjusted area under the curve [AUC]0-130 min -2.1, -1.1, and -0.6 mmol x h(-1) x l(-1); p < or = 0.0001). An even greater effect was observed with combination therapy (AUC0-130 min -2.5 mmol x h(-1) x l(-1); P < or = 0.0001 vs. metformin and placebo). All regimens were well tolerated. CONCLUSIONS: Nateglinide and metformin monotherapy each improved overall glycemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected FPG. In combination, nateglinide and metformin had complementary effects, improving HbA1c, FPG, and postprandial hyperglycemia.

Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study.

OBJECTIVE: The objective was to examine prospectively the association between low testosterone and sex hormone-binding globulin (SHBG) levels and the subsequent development of type 2 diabetes in men. RESEARCH DESIGN AND METHODS: Analyses were conducted on the cohort of the Massachusetts Male Aging Study, a population-based random sample of men aged 40-70. Of the 1,709 men enrolled in 1987-1989 (T1), 1,156 were followed up 7-10 years later (T2). Testosterone and SHBG levels at T1 were used to predict new cases of diabetes between T1 and T2. RESULTS: After controlling for potential confounders, diabetes at follow-up was predicted jointly and independently by lower baseline levels of free testosterone and SHBG. The odds ratio for future diabetes was 1.58 for a decrease of 1SD in free testosterone (4 ng/dl) and 1.89 for a 1SD decrease in SHBG (16 nmol/l), both significant at P < 0.02. CONCLUSIONS: Our prospective findings are consistent with previous, mainly cross-sectional reports, suggesting that low levels of testosterone and SHBG play some role in the development of insulin resistance and subsequent type 2 diabetes.

The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes.

Estrogens protect healthy women from cardiovascular disease. However, epidemiological data suggest that women with diabetes are denied the cardioprotection associated with estrogens. Whether or not hormonal replacement therapy (HRT) confers cardiovascular benefits in postmenopausal women with diabetes is not known. The aim of this study was to examine the effects of HRT on the microvascular reactivity and endothelial function of individuals with and without diabetes. We studied the following groups of individuals: premenopausal healthy women [n = 28, age 41 +/- 8 yr (mean +/- SD)], premenopausal women with type 2 diabetes (n = 16, age 43 +/- 6 yr); postmenopausal healthy women (n = 12, age 57 +/- 4 yr), postmenopausal women with diabetes (n = 17, age 62 +/- 5 yr); postmenopausal healthy women on HRT (n = 13, age 51 +/- 5 yr), postmenopausal women with diabetes on HRT (n = 11, age 57 +/- 7 yr). We used laser Doppler flowmetry to measure forearm cutaneous vasodilatation in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium independent). The endothelium-dependent vasodilation was significantly higher in premenopausal healthy women (180 +/- 67%; increase over baseline) compared to premenopausal diabetic women (87 +/- 41%; P < 0.001). endothelium-dependent vasodilation was also higher in postmenopausal healthy women on HRT (143 +/- 52) compared with postmenopausal diabetic women on HRT (86 +/- 61), postmenopausal healthy women without HRT (104 +/- 43), and postmenopausal diabetic women without HRT (74 +/- 28; P < 0.001). A similar pattern of responses was observed in the endothelium-independent vasodilation (premenopausal healthy women, 126 +/- 56; premenopausal diabetic women, 88 +/- 26; postmenopausal healthy women on HRT, 121 +/- 37; postmenopausal diabetic women on HRT, 88 +/- 41; postmenopausal healthy women without HRT, 84 +/- 36; and postmenopausal diabetic women without HRT, 73 +/- 36; P < 0.001). Soluble intercellular adhesion molecule (sICAM) was also measured among all the women with diabetes. Premenopausal women with diabetes (248.9 +/- 56 ng/ml) and postmenopausal women with diabetes on HRT (257.7 +/- 49 ng/ml) had lower sICAM levels compared with the postmenopausal diabetic women without HRT (346.4 +/- 149 ng/ml; P < 0.05). We conclude that menopausal status and type 2 diabetes are associated with impaired microvascular reactivity. HRT substantially improves microvascular reactivity in postmenopausal healthy women. In contrast, the effect of HRT on the microvascular reactivity of postmenopausal diabetic women is less apparent. However, the use of HRT among women with diabetes is associated with lower sICAM levels, suggesting an attenuation in endothelial activation.

Soluble intercellular adhesion molecule, vascular cell adhesion molecule, and impaired microvascular reactivity are early markers of vasculopathy in type 2 diabetic individuals without microalbuminuria.

OBJECTIVE: Using von Willebrand Factor (vWF) as a marker of endothelial function, previous studies have shown that the development of microalbuminuria is associated with the onset of endothelial dysfunction in individuals with type 2 diabetes. We tested the hypothesis that endothelial dysfunction is already evident in normoalbuminuric individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: We used laser Doppler imaging scanning to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine (endothelium-dependent) and 1% sodium nitroprusside (endothelium-independent). Multiple indicators of endothelial function--soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), vWF, and microvascular reactivity--were measured in 20 healthy control subjects, 45 normoalbuminuric (urinary albumin/creatinine ratio < 30 micrograms/mg) individuals with type 2 diabetes, and 14 microalbuminuric (urinary albumin/creatinine ratio between 30 and 300 micrograms/mg) individuals with type 2 diabetes. RESULTS: Serum sICAM and sVCAM levels were elevated in the normoalbuminuric (305 +/- 120, 851 +/- 284 ng/ml) and microalbuminuric (300 +/- 89, 845 +/- 252 ng/ml) individuals with diabetes when compared with the healthy control subjects (213 +/- 58, 661 +/- 176 ng/ml) (P < 0.01). Furthermore, the microvascular endothelium-dependent and -independent vasodilation was reduced in the normoalbuminuric (76 +/- 44, 70 +/- 33) (percent increase in perfusion over baseline) and microalbuminuric (74 +/- 41, 73 +/- 28) individuals with diabetes compared with healthy control subjects (126 +/- 67, 120 +/- 47) (P < 0.05). In contrast, plasma vWF was elevated only in the microalbuminuric individuals with diabetes (129 +/- 35%) compared with the normoalbuminuric individuals with diabetes (110 +/- 34) and healthy control subjects (111.3 +/- 39) (P < 0.05). On stepwise multivariate analysis, fasting blood glucose was the most important contributing factor to the variation in microvascular reactivity and sVCAM, whereas insulin resistance (by homeostasis model assessment) was the most important contributing factor to the variation in sICAM. Addition of all clinical and biochemical measures explained only 15-22% of the variation in sICAM, sVCAM, and microvascular reactivity. CONCLUSIONS: Multiple markers of endothelial dysfunction were evident in normoalbuminuric individuals with type 2 diabetes. The pathogenic process of vasculopathy in type 2 diabetes occurs early and may be operative before the development of microalbuminuria.

Exercise and insulin cause GLUT-4 translocation in human skeletal muscle.

Studies in rodents have established that GLUT-4 translocation is the major mechanism by which insulin and exercise increase glucose uptake in skeletal muscle. In contrast, much less is known about the translocation phenomenon in human skeletal muscle. In the current study, nine healthy volunteers were studied on two different days. On one day, biopsies of vastus lateralis muscle were taken before and after a 2-h euglycemic-hyperinsulinemic clamp (0.8 mU. kg(-1). min(-1)). On another day, subjects exercised for 60 min at 70% of maximal oxygen consumption (VO(2 max)), a biopsy was obtained, and the same clamp and biopsy procedure was performed as that during the previous experiment. Compared with insulin treatment alone, glucose infusion rates were significantly increased during the postexercise clamp for the periods 0-30 min, 30-60 min, and 60-90 min, but not during the last 30 min of the clamp. Plasma membrane GLUT-4 content was significantly increased in response to physiological hyperinsulinemia (32% above rest), exercise (35%), and the combination of exercise plus insulin (44%). Phosphorylation of Akt, a putative signaling intermediary for GLUT-4 translocation, was increased in response to insulin (640% above rest), exercise (280%), and exercise plus insulin (1,000%). These data demonstrate that two normal physiological conditions, moderate intensity exercise and physiological hyperinsulinemia approximately 56 microU/ml, cause GLUT-4 translocation and Akt phosphorylation in human skeletal muscle.

Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.

Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about changes in vascular reactivity in those at risk for developing type 2 diabetes. To address this situation, the vascular reactivity in both the micro- and macrocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degree relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impaired glucose tolerance (IGT), and 42 patients with type 2 diabetes without vascular complications (diabetes). Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent) and 1% sodium nitroprusside (SNP) (endothelium-independent), whereas high-resolution ultrasound images were used to measure brachial artery diameter changes during reactive hyperemia. Plasma concentrations of endothelin-1 (ET-1), von Willebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The vasodilatory responses to Ach, expressed as percent increase of blood flow over baseline, were reduced in relatives (98 +/- 48, mean +/- SD), IGT (94 +/- 52), and diabetes (74 +/- 45) compared with controls (126 +/- 67) (P < 0.001 controls versus relatives, IGT, and diabetes). The responses to SNP were similarly reduced: controls (123 +/- 46), relatives (85 +/- 46), IGT (83 +/- 48), and diabetes (65 +/- 31) (P < 0.001 controls versus relatives, IGT, and diabetes) as were the responses in the brachial artery diameter during reactive hyperemia: controls (13.7 +/- 6.1), relatives (10.5 +/- 6.7), IGT (9.8 +/- 4.5), and diabetes (8.4 +/- 5.0) (P < 0.01 controls versus relatives, IGT, and diabetes). Women had greater responses than men in both the micro- and macrovascular circulatory tests, but a similar progressive reduction was observed in both sexes with increasing degrees of glucose intolerance. A significant inverse correlation was found between microvascular reactivity and systolic blood pressure, fasting plasma glucose, HDL cholesterol, fasting plasma insulin, and homeostasis model assessment (HOMA) values, an index of insulin resistance. BMI and diastolic blood pressure had a significant inverse correlation only with endothelium-dependent vasodilation. In the macrocirculation, systolic blood pressure, HbA1c, HDL cholesterol, and HOMA had significant correlation with brachial artery diameter changes. Compared with control subjects, ET-1 was significantly higher in all groups, vWF was higher only in the diabetic group, sICAM levels were higher in the IGT and diabetic groups, while sVCAM concentrations were higher in the relatives and those with diabetes (P < 0.05). On stepwise multivariate analysis, age, sex, fasting plasma glucose, and BMI were the most important contributing factors to the variation of vascular reactivity. Addition of all clinical and biochemical measures explained only 32-37% of the variation in vascular reactivity. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes, even at a stage when normal glucose tolerance exists, and that factors in addition to insulin resistance may be operative.

Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes.

Total GLUT4 content in skeletal muscle from individuals with type 2 diabetes is normal; however, recent studies have demonstrated that translocation of GLUT4 to the plasma membrane is decreased in response to insulin stimulation. It is not known whether physical exercise stimulates GLUT4 translocation in skeletal muscle of individuals with type 2 diabetes. Five subjects (two men, three women) with type 2 diabetes and five normal control subjects (5 men), as determined by a standard 75-g oral glucose tolerance test, were recruited to determine whether an acute bout of cycle exercise activates the translocation of GLUT4 to the plasma membrane in skeletal muscle. Each subject had two open biopsies of vastus lateralis muscle; one at rest and one 3-6 weeks later from the opposite leg after 45-60 min of cycle exercise at 60-70% of VO2max. Skeletal muscle plasma membranes were prepared by subcellular fractionation, and GLUT4 content was determined by Western blotting. Plasma membrane GLUT4 increased in each subject in response to exercise. The mean increase in plasma membrane GLUT4 for the subjects with type 2 diabetes was 74 +/-20% above resting values, and for the normal subjects the increase was 71+/-18% above resting values. Although plasma membrane GLUT4 content was approximately 32% lower at rest and after exercise in the muscle of the subjects with type 2 diabetes, the differences were not statistically significant. We conclude that in contrast to the previously reported defect in insulin-stimulated GLUT4 translocation in skeletal muscle of individuals with type 2 diabetes, a single bout of exercise results in the translocation of GLUT4 to the plasma membrane in skeletal muscle of individuals with type 2 diabetes. These data provide the first direct evidence that GLUT4 translocation is an important cellular mechanism through which exercise enhances skeletal muscle glucose uptake in individuals with type 2 diabetes.

Surgery-induced insulin resistance in human patients: relation to glucose transport and utilization.

To investigate the underlying molecular mechanisms for surgery-induced insulin resistance in skeletal muscle, six otherwise healthy patients undergoing total hip replacement were studied before, during, and after surgery. Patients were studied under basal conditions and during physiological hyperinsulinemia (60 microU/ml). Biopsies of vastus lateralis muscle were used to measure GLUT-4 translocation, glucose transport, and glycogen synthase activities. Surgery reduced insulin-stimulated glucose disposal (P < 0.05) without altering the insulin-stimulated increase in glucose oxidation or suppression of endogenous glucose production. Preoperatively, insulin infusion increased plasma membrane GLUT-4 in all six subjects (P < 0.05), whereas insulin-stimulated GLUT-4 translocation only occurred in three patients postoperatively (not significant). Moreover, nonoxidative glucose disposal rates and basal levels of glycogen synthase activities in muscle were reduced postoperatively (P < 0.05). These findings demonstrate that peripheral insulin resistance develops immediately postoperatively and that this condition might be associated with perturbations in insulin-stimulated GLUT-4 translocation as well as nonoxidative glucose disposal, presumably at the level of glycogen synthesis.

Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats.

Insulin-dependent diabetes in rats is characterized by abnormalities of post-binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the kidney capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes.

Epinephrine and insulin stimulate different mitogen-activated protein kinase signaling pathways in rat skeletal muscle.

Little is known about the regulation of the mitogen-activated protein (MAP) kinase signaling cascades by hormonal stimulation in vivo. The extracellular signal-regulated kinase (ERK) and the c-jun kinase (JNK) are two MAP kinase signaling pathways that could play a role in the cellular response to hormones such as insulin and epinephrine. We studied the effects of insulin (20 U/rat) and epinephrine (25 microg/100 g body wt) injected in vivo on ERK and JNK signaling in skeletal muscle from Sprague-Dawley rats. Insulin significantly increased ERK phosphorylation and the activity of its downstream substrate, the p90 ribosomal S6 kinase 2 (RSK2), by 1.4-fold, but it had no effect on JNK activity. In contrast, epinephrine had no effect on ERK phosphorylation or RSK2 activity, but it increased JNK activity by twofold, an effect that was inhibited by the presence of combined alpha and beta blockade. Furthermore, the phosphorylation of both p46 and p55 isoforms of JNK, measured by phosphospecific antibody, was increased severalfold. The activity and phosphorylation of MAP kinase kinase (MKK)-4, an upstream regulator of JNK, was unchanged by epinephrine. Incubation of isolated soleus muscles in vitro with epinephrine (10(-5) mol/l) also increased JNK activity by twofold. These data are the first to demonstrate that epinephrine can increase JNK activity. Insulin and epinephrine have different effects on MAP kinase signaling pathways in skeletal muscle, which may be one of the underlying molecular mechanisms through which these hormones regulate opposing metabolic functions.

Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group.

OBJECTIVE: To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. RESEARCH DESIGN AND METHODS: There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. RESULTS: Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.

Aerobic exercise capacity remains normal despite impaired endothelial function in the micro- and macrocirculation of physically active IDDM patients.

The aim of the present study was to examine if diabetes in the absence of neuropathy affects the exercising capacity of IDDM patients, and whether regular, intense training has a beneficial effect on endothelial function. Five groups of subjects were studied: 23 healthy control subjects who exercised regularly (age 33 +/- 6 years), 23 nonneuropathic type 1 diabetic patients who exercised regularly (age 33 +/- 6 years, IDDM duration 11 +/- 8 years), 7 neuropathic type 1 diabetic patients who exercised regularly (age 36 +/- 7 years, IDDM duration 22 +/- 8 years), 18 healthy subjects who did not exercise regularly (age 34 +/- 7 years), and 5 nonneuropathic type 1 diabetic patients who did not exercise regularly (age 31 +/- 4 years, IDDM duration 20 +/- 3 years). All groups were matched for age, sex, and body weight. No differences existed in the energy expenditure per week in physical activity among the three exercising groups or between the two nonexercising groups. The maximal oxygen uptake was similar between control and diabetic nonneuropathic exercisers, and among diabetic neuropathic exercisers, control nonexercisers, and diabetic nonexercisers; however, a significant difference existed between the first two and the last three groups (P < 0.0001). A stepwise increase was found in the resting heart rate among the groups, ranging from the lowest in control exercisers to the highest in diabetic nonexercisers, but the maximal heart rate was lower only in diabetic neuropathic exercisers compared with all other groups (P < 0.05). Assessments of endothelial function in both macro- and microcirculation were performed in 12 control exercisers, 10 diabetic nonneuropathic exercisers, 5 diabetic neuropathic exercisers, 17 control nonexercisers, and 4 diabetic nonexercisers. When all diabetic patients were considered as one group and all control subjects as another, the microcirculation endothelial function in the diabetic group was reduced compared with the control subjects (91 +/- 49 vs. 122 +/- 41% flux increase over baseline; P < 0.05). In contrast, no differences existed among the three diabetic groups or between the two control groups. Similarly, in macrocirculation, a reduced response during reactive hyperemia was observed in the diabetic patients compared with control subjects (7.0 +/- 4.5 vs. 11.2 +/- 6.6% diameter increase; P < 0.05), whereas again no difference existed among the three diabetic groups or between the two control groups. These data suggest that diabetes per se does not affect aerobic exercise capacity (VO2max) in physically active individuals, but is reduced in the presence of neuropathy. In addition, regular exercise training involving the lower extremities does not improve the endothelial function in the micro- and macrocirculation of the nonexercised upper extremity in type 1 diabetic patients.

CL-316,243, a beta3-specific adrenoceptor agonist, enhances insulin-stimulated glucose disposal in nonobese rats.

Administration of the murine-selective beta3 adrenoceptor agonist CL-316,243 corrects obesity and elevated blood glucose in diabetic rodents. This antiobesity effect is attributed to an increase in the thermogenic activity of brown adipose tissue (BAT). The antidiabetic effect is unknown, but has been attributed to the decline in body weight and plasma free fatty acids (FFAs). This study using the euglycemic-hyperinsulinemic clamp method was performed in nonobese, nondiabetic Sprague-Dawley rats fed normal rodent chow to determine if the beta3 agonist could improve insulin sensitivity and/or responsiveness in the absence of weight loss or lowering of circulating FFAs. Subcutaneous miniosmotic pumps delivered either saline to control or 1 mg x kg(-1) x day(-1) of CL-316,243 for 10-12 days. Fed plasma glucose, insulin, and FFA levels were similar between the groups. Significant increases in food consumption, resting metabolic rates, and body core temperatures occurred, but only after 7 days of treatment. A 14% decrease in the respiratory quotient was also observed. Plasma glucose and insulin excursions in response to an oral glucose load (2 g/kg) on day 11 were unaltered. Cl-316,243 treatment resulted in a decrease in abdominal and epididymal white fat pad weights, while interscapular brown adipose tissue (IBAT) weight doubled. Basal and insulin-stimulated whole-body glucose disposal rates were increased, while hepatic glucose output was suppressed to a greater extent in the CL-316,243 animals after 10 days of uninterrupted treatment. Chronic treatment with CL-316,243 resulted in an increase in basal and insulin-stimulated [3H]2-deoxyglucose (2-DG) uptake by the retroperitoneal and epididymal white tissue and IBAT, but skeletal muscle 2-DG uptake under the same conditions was unaltered. These studies demonstrate that treatment with CL-316,243 improves basal and insulin-stimulated glucose disposal, and these effects occurred in the absence of a decrease in body weights and FFA concentrations. A particularly interesting observation was that the tissues responsible for this effect were white and brown adipose tissue, while skeletal muscle remained unaffected.

Long-term normalization of GLUT-4 protein content in skeletal muscle of diabetic rats following islet transplantation.

Skeletal muscle GLUT-4 content is decreased in streptozotocin (STZ)-diabetic rats. This decrease is associated with impairment in glucose transport across the plasma membrane. In this study we investigated whether islet transplantation might normalize GLUT-4 content. Transplantation of syngeneic islets restored long-term near-normoglycemia in STZ-diabetic Lewis rats. Transplanted rats, followed up to 6 months, maintained slightly but significantly higher fasting and fed glucose levels when compared with age-matched normal controls. Although fasting insulin levels of transplanted rats were significantly higher than those of controls, insulin levels did not increase significantly with feeding. Plasma glucose levels following an oral glucose load (2 g/kg) were only slightly higher than in normal controls 2 months after transplantation, whereas after 6 months more severe glucose intolerance was detected. Transplanted rats completely lost the first-phase insulin release in response to i.v. glucose although they showed an increased second phase and preserved response to arginine. Six months after transplantation, endocrine beta cell mass of the grafts was similar to pretransplantation values. GLUT-4 protein content in skeletal muscle homogenates was reduced in untreated diabetic animals whereas it was completely restored by islet transplantation. In conclusion, achievement of long-term nearnormoglycemia after islet transplantation was associated with complete normalization of skeletal muscle GLUT-4 content in the diabetic animals, even in the presence of abnormal glucose tolerance and an altered pattern of insulin secretion.

Glucose ingestion causes GLUT4 translocation in human skeletal muscle.

In humans, ingestion of carbohydrates causes an increase in blood glucose concentration, pancreatic insulin release, and increased glucose disposal into skeletal muscle. The underlying molecular mechanism for the increase in glucose disposal in human skeletal muscle after carbohydrate ingestion is not known. We determined whether glucose ingestion increases glucose uptake in human skeletal muscle by increasing the number of glucose transporter proteins at the cell surface and/or by increasing the activity of the glucose transporter proteins in the plasma membrane. Under local anesthesia, approximately 1 g of vastus lateralis muscle was obtained from six healthy subjects before and 60 min after ingestion of a 75-g glucose load. Plasma membranes were isolated from the skeletal muscle and used to measure GLUT4 and GLUT1 content and glucose transport in plasma membrane vesicles. Glucose ingestion increased the plasma membrane content of GLUT4 per gram muscle (3,524 +/- 729 vs. 4,473 +/- 952 arbitrary units for basal and 60 min, respectively; P < 0.005). Transporter-mediated glucose transport into plasma membrane vesicles was also significantly increased (130 +/- 11 vs. 224 +/- 38 pmol.mg-1.s-1; P < 0.017), whereas the calculated ratio of glucose transport to GLUT4, an indication of transporter functional activity, was not significantly increased 60 min after glucose ingestion (2.3 +/- 0.4 vs. 3.0 +/- 0.5 pmol.GLUT4 arbitrary units-1.s-1; P < 0.17). These results demonstrate that oral ingestion of glucose increases the rate of glucose transport across the plasma membrane and causes GLUT4 translocation in human skeletal muscle. These findings suggest that under physiological conditions the translocation of GLUT4 is an important mechanism for the stimulation of glucose uptake in human skeletal muscle.