Marian Mokan

Role of Reduced Suppression of Glucose Production and Diminished Early Insulin Release in Impaired Glucose Tolerance

BACKGROUND Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. METHODS We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. RESULTS After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. CONCLUSIONS Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.

Interaction between glucose and free fatty acid metabolism in human skeletal muscle.

The mechanism by which FFA metabolism inhibits intracellular insulin-mediated muscle glucose metabolism in normal humans is unknown. We used the leg balance technique with muscle biopsies to determine how experimental maintenance of FFA during hyperinsulinemia alters muscle glucose uptake, oxidation, glycolysis, storage, pyruvate dehydrogenase (PDH), or glycogen synthase (GS). 10 healthy volunteers had two euglycemic insulin clamp experiments. On one occasion, FFA were maintained by lipid emulsion infusion; on the other, FFA were allowed to fall. Leg FFA uptake was monitored with [9,10-3H]-palmitate. Maintenance of FFA during hyperinsulinemia decreased muscle glucose uptake (1.57 +/- 0.31 vs 2.44 +/- 0.39 mumol/min per 100 ml tissue, P < 0.01), leg respiratory quotient (0.86 +/- 0.02 vs 0.93 +/- 0.02, P < 0.05), contribution of glucose to leg oxygen consumption (53 +/- 6 vs 76 +/- 8%, P < 0.05), and PDH activity (0.328 +/- 0.053 vs 0.662 +/- 0.176 nmol/min per mg, P < 0.05). Leg lactate balance was increased. The greatest effect of FFA replacement was reduced muscle glucose storage (0.36 +/- 0.20 vs 1.24 +/- 0.25 mumol/min per 100 ml, P < 0.01), accompanied by decreased GS fractional velocity (0.129 +/- 0.26 vs 0.169 +/- 0.033, P < 0.01). These results confirm in human skeletal muscle the existence of competition between glucose and FFA as oxidative fuels, mediated by suppression of PDH. Maintenance of FFA levels during hyperinsulinemia most strikingly inhibited leg muscle glucose storage, accompanied by decreased GS activity.

Induction of Hypoglycemia Unawareness by Asymptomatic Nocturnal Hypoglycemia

Hypoglycemia has been incriminated as a possible factor responsible for development of the hypoglycemia unawareness phenomenon in patients with type I diabetes. Many patients with this condition, however, do not have a history of recent hypoglycemia. Because asymptomatic nocturnal hypoglycemia commonly occurs in type I diabetes, we tested the hypothesis that such episodes might be capable of inducing this phenomenon. Accordingly, autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function were assessed during standardized insulin-induced hypoglycemia in 10 normal volunteer subjects on two occasions—once after induction of asymptomatic nocturnal hypoglycemia and once after control studies in which saline rather than insulin was infused overnight. Compared with control experiments, asymptomatic nocturnal hypoglycemia increased the threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction during subsequent hypoglycemia (all, P < 0.05). These results indicate that asymptomatic hypoglycemia may induce hypoglycemia unawareness and, thus, may explain why not every patient with this condition has a history of prior hypoglycemia. Our results therefore support the concept that in type I diabetes this phenomenon may be largely attributable to antecedent hypoglycemia.

Effect of Hyperketonemia and Hyperlacticacidemia on Symptoms, Cognitive Dysfunction, and Counterregulatory Hormone Responses During Hypoglycemia in Normal Humans

The brain usually depends almost exclusively on glucose for its energy requirements. During hypoglycemia associated with prolonged fasting or strenuous exercise, circulating ketone-body and lactate levels increase severalfold; in both situations, certain signs and symptoms of hypoglycemia are diminished. Therefore, to test the hypothesis that hyperketonemia or hyperlacticacidemia of the magnitude seen during certain clinical situations can substitute for glucose as an energy source for the brain and alter physiological responses to hypoglycemia, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function during standardized insulin-induced hypoglycemia in normal volunteers with and without infusion of (β-hydroxybutyrate (BOHB) or lactate designed to reproduce circulating levels of these substrates seen during prolonged fasting and strenuous exercise. Compared with paired control experiments, infusion of BOHB and lactate increased the glycemic threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction (all P < 0.05). The hypoglycemic threshold for autonomic symptoms increased from 3.8 ± 0.1 to 3.1 ± 0.2 mmoM during BOHB infusion and from 3.7 ± 0.1 to 2.8 ± 0 . 1 mmol<1 during lactate infusion, and the threshold for neuroglycopenic symptoms increased from 2.8 ± 0.1 to 2.4 ± 0.1 and 2.3 ± 0.1 mmol/1, respectively. The magnitude for autonomic symptoms decreased from 12 ± 2 and 11 ± 1 to 6 ± 2 and 4 ± 1 during BOHB and lactate infusion, respectively. Neuroglycopenic symptoms decreased from 11 ± 2 to 3 ± 1 during both series of experiments. Infusion of BOHB and lactate-reduced responses for all counterregulatory hormones, the reduction being the greatest for epinephrine (∼57 and 73%, during BOHB and lactate infusion, respectively) and least for cortisol (7sim;28 and 29%, respectively). These results indicate that under certain clinical conditions, BOHB and lactate may substitute for glucose as a fuel for the brain and alter physiological responses to hypoglycemia.

Intracellular Defects in Glucose Metabolism in Obese Patients With NIDDM

Skeletal muscle insulin resistance in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) is characterized by decreased glucose uptake. Although reduced glycogen synthesis is thought to be the predominant cause for this deficit, studies supporting this notion often have been conducted at supraphysiological insulin concentrations in which glucose storage is the overwhelming pathway of glucose disposal. However, at lower, more physiological insulin concentrations, decreased muscle glucose oxidation could play a significant role. This study was undertaken to determine whether, under euglycemic conditions, insulin resistance for leg muscle glucose uptake in NIDDM patients is due primarily to decreased glucose storage or to oxidation. The leg balance technique and leg indirect calorimetry were used under steady-state euglycemic conditions to estimate muscle glucose uptake, storage, and oxidation in eight moderately obese NIDDM patients and eight matched-control subjects. Leg muscle biopsies also were performed to determine whether alterations in muscle pyruvate dehydrogenase or glycogen synthase activities could explain defects in glucose oxidation or storage. At insulin concentrations of ∼ 500–600 pM, leg glucose uptake, oxidation, and storage in the NIDDM group (2.03 ± 0.42, 1.00 ± 0.13, 0.66 ± 0.36 μmol · min−1 · 100 ml−1) were significantly lower (P < 0.05) than rates in control subjects (5.14 ± 0.64, 1.92 ± 0.17, 2.80 ± 0.54). Pyruvate dehydrogenase and glycogen synthase activities were also decreased, consistent with the in vivo metabolic defects. The average deficit in leg glucose uptake in NIDDM was 3.11 ± 0.42 μmol · min−1 μ 100 ml−1. Of this deficit, 66% (2.14 ± 0.36 μmol min−1 · 100 ml−1) was due to decreased leg glucose storage and 33% (0.92 ± 0.13 μmol min−1 · 100 ml−1) to decreased leg glucose oxidation. Our findings confirm that decreased muscle glucose storage during hyperinsulinemia is the largest defect in glucose metabolism but also reveal a major defect in glucose oxidation. These studies reinforce the notion that muscle insulin resistance in obese NIDDM patients is characterized by a panoply of intracellular defects in glucose metabolism and insulin action.

Metabolic Pathways of Glucose in Skeletal Muscle of Lean NIDDM Patients

OBJECTIVE To characterize the ability of insulin to activate the skeletal muscle metabolic pathways of glucose storage, oxidation, and glycolysis in normal weight patients with NIDDM and nondiabetic volunteer subjects closely matched for age, sex, relative weight, and body composition. RESEARCH DESIGN AND METHODS Ten patients with NIDDM (body mass index 23.9 ± 0.74 kg/m2) and 8 nondiabetic volunteer subjects (body mass index 23.4 ± 0.41 kg/m2) were studied. Leg muscle glucose uptake, non-oxidized glycolysis, glucose oxidation, and glucose storage were determined during euglycemic-hyperinsulinemic clamp experiments using the leg balance technique combined with leg indirect calorimetry. Percutaneous muscle biopsies were obtained to assay insulin stimulation of muscle glycogen synthase activity as a biochemical marker of insulin action. RESULTS During hyperinsulinemic clamp experiments, leg glucose uptake was equivalent in NIDDM patients and nondiabetic subjects (6.38 ± 1.14 vs. 6.41 ± 0.73 μmol.min−1 · 100 ml tissue−1), as were rates of leg glucose oxidation (1.63 ± 0.25 vs. 2.14 ± 0.17 μmol.min−1 · 100 ml tissue−1) and leg glucose storage (4.35 ± 1.10 vs. 3.48 ± 0.65 μmol·min−1 · 100 ml tissue−1). The combined net balance of lactate and Ala (non-oxidized glycolysis) was lower in NIDDM patients (−0.39 ± 0.06 vs. −0.79 ± 0.11 μmol·min−1 · 100 ml tissue−1, P = 0.01). Muscle glycogen synthase was activated to a similar extent during the hyperinsulinemic clamp in NIDDM patients and nondiabetic volunteer subjects, through basal glycogen synthase activity was lower in NIDDM patients. Nondiabetic subjects and NIDDM patients who were withdrawn from sulfonylurea therapy had impaired insulin secretion during a 75-g oral glucose tolerance test, with similar basal levels as nondiabetic subjects (54 ± 12 vs. 42 ± 6 pM), but reduced peak insulin levels (126 ± 30 vs. 468 ± 102 pM, P < 0.01). CONCLUSIONS Detailed in vivo and in vitro assessment of insulin regulation of skeletal muscle glucose metabolism in lean NIDDM patients indicates that insulin action is intact in the muscle tissue of these patients.

First Evidence: TRAP-Induced Platelet Aggregation Is Reduced in Patients Receiving Xabans:

The availability of direct oral anticoagulants has caused a paradigm shift in the management of thrombosis. Rivaroxaban and apixaban are 2 direct oral anticoagulants whose target specificity is activated factor X (FXa). However, it is still not fully understood if and how xabans impact platelet function. This observational study aimed to assess the in vitro platelet function in patients with atrial fibrillation receiving xabans. This was a single-center study quantifying platelet aggregation in 41 patients treated with apixaban or rivaroxaban by light transmission aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly lower 2 hours after taking rivaroxaban or apixaban compared to baseline value (56.15% [8.53%] vs 29.51% [12.9%]; P = .000). Moreover, concomitant use of angiotensin-converting enzyme blockers, proton pump inhibitors, and statins reduces the efficiency of xabans. The TRAP-induced platelet aggregation was reduced in patients with cardiovascular disease 2 hours after receiving xabans.

Apixaban - Metabolism, Pharmacologic Properties and Drug Interactions

BACKGROUND Apixaban is an oral, potent, highly selective, reversible and direct inhibitor of activated coagulation factor X, that is the end point of the intrinsic and extrinsic coagulation pathway. Additionally, apixaban has the capacity to indirectly inhibit thrombin-induced platelet aggregation. This new oral anticoagulant represents an immediate-release form of peroral drug with quick dissolution, linear pharmacokinetics, good bioavailability and rapid onset and offset of action. No clinically relevant age- or sex-dependent difference in the apixaban pharmacokinetics and pharmacodynamics which would lead to the modification of the dose exists, apixaban may even be administered with or without food. Its elimination is mediated by metabolism, renal elimination of unmodified drug and excretion in the gastrointestinal tract. OBJECTIVE The authors aim to provide a review of currently available literature about apixaban. METHOD The authors summed-up the data from the scientific journals related to thrombosis and hemostasis and searched the available databases. RESULTS AND CONCLUSION Apixaban has many advantages including predictable pharmacokinetics and pharmacodynamics, low number of drug and food interactions, and relatively wide therapeutic window.

Metabolic Syndrome in Rheumatoid Arthritis

Abstract Inflammation is a key component of obesity and type 2 diabetes mellitus also as risk factors of cardiovascular disease. Patients with chronic inflammatory diseases such as rheumatoid arthritis or systemic lupus erythematosus have an increased risk of cardiovascular diseases. The expected higher prevalence of metabolic syndrome and its components in rheumatic diseases (such as possible cause of increased cardiovascular risk) was confirmed in rheumatoid arthritis, systemic lupus, ankylosing spondylitis and psoriatic arthritis. The aim of our study was to assess the relationship of rheumatoid arthritis to increased cardiovascular risk in the presence of risk factors involved in complex of metabolic syndrome, including prediabetic state, central obesity, atherogenic dyslipidemia, and hypertension. In the sample of patients with rheumatoid arthritis, the prevalence of the metabolic syndrome according to IDF, AHA/NHLBI and also NCEP ATPIII criteria compared with the Slovak population in all age groups is higher. In patients older than 60 years according to IDF criteria was more than 55 %. Patients treated with methotrexate had the lowest prevalence of metabolic syndrome, even lower than the control population. The most frequented component of the metabolic syndrome was obesity (whether in the evaluation of waist circumference or BMI). Also, patients with higher inflammatory activity (evaluated by CRP) had a higher prevalence of metabolic syndrome.

Insulin Treatment Inhibits PAI-1 Production in NIDDM Patients with Endothelial Dysfunction

We examined 34 non-insulin-dependent diabetes mellitus (NIDDM) patients treated with sulfonylurea regimens, 24 NIDDM patients with 2-3 months long-acting insulin treat ment and 19 age-matched normoinsulinemic healthy controls. NIDDM patients were divided into two subgroups, with and without endothelial dysfunction according to von Willebrand factor level 0.14 IU/mL. There were significant differences in PAI-1 levels among patients without endothelial dysfunction treated by sulfonylurea agents (median 48.1, range 14-108 ng/ mL) or insulin (27.9, 2-53 ng/mL) and patients with endothe lial dysfunction treated by sulfonylurea regimens (80.7, 43-217 ng/mL) or insulin, respectively, (16.7, 7-34 ng/mL) (analysis of variance p < .001). NIDDM subgroups were not different in metabolic parameters (C-peptide and triglyceride levels, body mass index) and platelet activation marker (platelet factor 4 values). von Willebrand Factor and thrombomodulin levels were elevated in groups with endothelial dysfunction (analysis of variance p < .001, p = .025, respectively). Insulin treatment was accompanied by decreased PAI-1 levels especially in pa tients with endothelial dysfunction. Insulin is the inhibitor of endothelial PAI-1 production induced by cytokines. Therefore, we suggest that long-term insulin application may decrease PAI-1 levels by direct inhibitive action on the endothelial PAI-1 compartment. This hypothesis requires further research.