Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle.

AIMS/HYPOTHESIS: A role for increased activity of the innate immune system in the pathogenesis of insulin resistance is supported by a number of studies. The current study assessed the potential role of the lipopolysaccharide receptor known as Toll-like receptor-4 (TLR-4), a component of the innate immune system, in mediating lipid-induced insulin resistance in skeletal muscle. METHODS: The effects of TLR-4 inhibition/deletion on lipid-induced insulin resistance was determined in skeletal muscle of TLR-4 null mice in vivo and in rat L6 myotubes in vitro. RESULTS: In mice, acute hyperlipidaemia induced skeletal muscle insulin resistance, but a deletion of TLR-4 conferred significant protection against these effects. In L6 myotubes, inhibition of TLR-4 activity substantially reduced the capacity of the saturated fatty acid palmitate to induce insulin resistance. Importantly, palmitate activated the nuclear factor kappaB (NFkappaB) pathway in L6 myotubes and mouse skeletal muscle, and these effects were blocked by inhibition of TLR-4 in L6 myotubes and absence of TLR-4 in skeletal muscle. Furthermore, inhibition of the NFkappaB pathway downstream of TLR-4 in L6 myotubes also protected against the induction of insulin resistance by palmitate. CONCLUSIONS/INTERPRETATION: Inhibition or absence of TLR-4 confers protection against the detrimental effects of lipids on skeletal muscle insulin action, and these effects are associated with a prevention of the activation of the NFkappaB pathway by lipids. Importantly, inhibition of the NFkappaB pathway in myotubes downstream of TLR-4 also protects against lipid-induced insulin resistance, suggesting a mechanism by which reduced TLR-4 activity confers beneficial effects on insulin action.

Chemotherapy of leishmaniasis Part VI: synthesis and bioevaluation of some novel terpenyl S,N- and N,N-acetals.

Some novel terpene based oxoketene S,N-acetals 2(a-g) and N,N-acetals 3(a-c) have been synthesized from oxoketene dithioacetal 1. The compounds were screened for their in vivo antileishmanial activity. Some of the compounds showed 50-70% inhibition in the hamster model.

Management of decompensated diabetes. Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome.

DKA and HHS represent two extremes in the spectrum of decompensated diabetes mellitus. Their pathogenesis is related to absolute or relative deficiency in insulin levels and elevations in insulin counterregulatory hormones that lead to altered metabolism of carbohydrate, protein, and fat and varying degrees of osmotic diuresis and dehydration, ketosis, and acidosis. In DKA, insulin deficiency and ketoacidosis are the prominent features of the clinical presentation, and insulin therapy is the cornerstone of therapy. In HHS, hyperglycemia, osmotic diuresis, and dehydration are the prominent features, and fluid replacement is the cornerstone of therapy. As many as one-third of patients may have mixed features of both DKA and HHS. Because the three-pronged approach to therapy for either DKA or HHS consists of fluid administration, intravenous insulin infusion, and electrolyte replacement, mixed cases are managed using the same approach. The therapeutic regimen is tailored according to the prominent clinical features present. In adult patients with mixed features, fluids may be administered more rapidly than they would be in younger patients, or in patients with DKA alone, because the risk for fatal cerebral edema in adults is low and the consequences of undertreatment include vascular occlusion and increased mortality. In younger patients with mixed features, rapid correction of metabolic abnormalities and, consequently, of hyperosmolarity by administration of hypotonic fluids and insulin should be avoided to decrease the risk for precipitating cerebral edema. In addition, if ketoacidosis has been a prominent feature in a mixed case, the patient may have type 1 diabetes with no residual pancreatic islet beta cell secretion and may subsequently need ongoing, life-long insulin therapy after resolution of the acute episode of decompensated diabetes. ICU admission is indicated in the management of DKA, HHS, and mixed cases in the presence of cardiovascular instability, inability to protect the airway, obtundation, the presence of acute abdominal signs or symptoms suggestive of acute gastric dilatation, or if there is not adequate capacity on the floor unit to administer the intravenous insulin infusion and to provide the frequent and necessary monitoring that must accompany its use.

Normal blood flow response and vasomotion in the diabetic Charcot foot.

Vasomotion, the spontaneous rhythmic contraction exhibited by small arteries and arterioles is dysregulated in patients with diabetic neuropathy. We examined the relationship between Charcot arthropathy and vasomotion at the dorsum of the foot. We studied nine diabetic patients with clinically diagnosed neuropathy and Charcot arthropathy in 13 feet (n=13), twelve subjects with diabetic neuropathy and no Charcot deformity (n=12), and 11 healthy controls (n=11). Following neuropathy assessment, blood flow was measured by laser Doppler flowmetry with local skin warming. Fast Fourier transformation was performed to provide an index of vasomotion. Subjects with Charcot osteoarthropathy had more severe somatic neuropathy and higher circulating levels of serum calcium (9.8+/-0.1 versus 9.3+/-0.1 mg/dL). Raising local temperature increased skin blood flow and vasomotion in both control subjects and Charcot subjects, but not in diabetic patients with neuropathy alone (p < 0.05 for blood flow, p < 0.02 for vasomotion). Patterns of peripheral vasomotion and blood flow which are clearly disordered in diabetic neuropathy are intact in patients with a Charcot osteoarthropathy, despite a more severe sensory nerve impairment. These findings suggest that the loss of peripheral blood flow and vasomotion often seen in diabetic neuropathy may actually be protective against Charcot arthropathy by preventing bone resorption. It remains unclear then whether the Charcot arthropathy is a direct result of a failure to decrease blood flow to bone, or is the manifestation of some other pathology.

Impairment of peripheral blood flow responses in diabetes resembles an enhanced aging effect.

OBJECTIVE: To test the hypothesis that skin blood flow responses in the fingertip of diabetic patients are impaired and to examine the role of aging in both healthy control subjects and diabetic patients. RESEARCH DESIGN AND METHODS: We measured cutaneous blood flow using laser Doppler techniques in 40 people with diabetes and in 20 age- and sex-matched healthy control subjects. To induce vasoconstriction, subjects were asked to perform three 1-min stressor tasks: mental arithmetic, contralateral hand grip, and immersion of the contralateral hand in ice water. To induce vasodilatation, a local heat stimulus of 45 degrees C was applied for 5 min. RESULTS: Basal blood flow did not differ between groups, but vasoconstrictive responses induced by arithmetic or immersion of the contralateral hand in ice-cold water and vasodilatation induced by local heating were severely impaired in diabetic subjects, compared with healthy control subjects (P < 0.01). These responses correlated with autonomic nerve function and deteriorated significantly with advancing age in control subjects, but not in diabetic subjects. Blood flow in younger diabetic subjects resembled that of older control subjects. CONCLUSIONS: These data demonstrate that diabetes has effects on precapillaries that may by direct or mediated via autonomic nerves, which result in a deficit that resembles premature aging.