Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots.

Chronic hepatitis C (CHC) is associated with lipid-related changes and insulin resistance; the latter predicts response to antiviral therapy, liver disease progression and the risk of diabetes. We sought to determine whether insulin sensitivity improves following CHC viral eradication after antiviral therapy and whether this is accompanied by changes in fat depots or adipokine levels. We compared 8 normoglycaemic men with CHC (genotype 1 or 3) before and at least 6 months post viral eradication and 15 hepatitis C antibody negative controls using an intravenous glucose tolerance test and two-step hyperinsulinaemic-euglycaemic clamp with [6,6-(2) H2 ] glucose to assess peripheral and hepatic insulin sensitivity. Magnetic resonance imaging and spectroscopy quantified abdominal fat compartments, liver and intramyocellular lipid. Peripheral insulin sensitivity improved (glucose infusion rate during high-dose insulin increased from 10.1 ± 1.6 to 12 ± 2.1 mg/kg/min/, P = 0.025), with no change in hepatic insulin response following successful viral eradication, without any accompanying change in muscle, liver or abdominal fat depots. There was corresponding improvement in incremental glycaemic response to intravenous glucose (pretreatment: 62.1 ± 8.3 vs post-treatment: 56.1 ± 8.5 mm, P = 0.008). Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid-binding protein and lipocalin-2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance.

Is postprandial hypertriglyceridaemia in relatives of type 2 diabetic subjects a consequence of insulin resistance?

BACKGROUND: Higher postprandial triglyceride responses reported in first degree relatives of people with type 2 diabetes (REL) were postulated to be the result of an early, possibly intrinsic, defect in oral lipid handling. The postprandial triglyceride response to high fat meals (HFM) in normal subjects is reduced by the insulin response to dietary carbohydrate (CHO) in the meal. The aims of this study were to examine whether (1) insulin resistance is associated with an intrinsic defect in triglyceride handling in insulin-resistant REL and (2) insulin resistance is associated with altered triglyceride handling after HFM with high CHO content. MATERIALS AND METHODS: Postprandial responses to a HFM in normolipidaemic, normoglycaemic REL were compared with subjects without a family history of diabetes mellitus (CON). Over 6 h, the insulin, glucose, triglyceride and nonesterified fatty acid (NEFA) responses after a high fat (80 g fat), low CHO (HFM-LC; 20 g CHO, 4250 kJ) meal and a high fat, high CHO (HFM-HC; 100 g CHO, 5450 kJ) meal were examined. RESULTS: The 10 (7F/3M) REL were significantly more insulin-resistant, determined by glucose infusion during a hyperinsulinaemic euglycaemic clamp than the 10 (5F/5M) CON (glucose infusion rate 44.6 +/- 4.9 vs. 60.0 +/- 4.8 micromol min(-1) kg FFM(-1), P = 0.037). Subjects were similar for age and body mass index (BMI). The triglyceride increments after the HFM-LC were similar in both, peaking at 180-240 min (Delta0.77 +/- 0.11 mmol L(-1)), demonstrating no postprandial defect in REL, despite insulin resistance. There was a significantly lower postprandial triglyceride response in CON following the HFM-HC compared with the HFM-LC, but not in REL. In contrast, the higher insulin level during the HFM-HC was associated with significantly greater NEFA level suppression than in the HFM-LC (2.13 +/- 0.51 vs. 0.70 +/- 0.35 mmol L(-1), P = 0.03), only in the REL. CONCLUSIONS: These results are inconsistent with a primary aetiological role for postprandial hypertriglyceridaemia in already insulin resistant type 2 diabetic REL, but raise the possibility that this potentially atherogenic manifestation is secondary to insulin resistance lessening VLDL production and/or release from the liver.

Electrical and chemical activation of the mesencephalic and subthalamic locomotor regions in freely moving rats.

The locomotor activity of freely moving rats was increased by electrical stimulation of brainstem sites, including the pedunculopontine nucleus, a major component of the mesencephalic locomotor region (MLR), and sites located in the subthalamic locomotor region (SLR), which is in the area of the zona incerta (ZI) dorsomedial to the subthalamic nucleus. Injections to the MLR of glycine, an inhibitory transmitter of the spinal cord and brainstem, had no effect on locomotion, nor did strychnine sulfate, a glycine antagonist. Unilateral injections of the excitatory amino acid, N-methyl-D-aspartic acid (NMDA), and kainic acid, a glutamate analogue, into the MLR produced an increase in locomotion not seen with glutamate, an excitatory amino acid, into the same area. A still greater response, having a later onset than NMDA but also a longer duration, was produced by administration of picrotoxin and bicuculline methiodide, GABA antagonists, to the MLR. Carbachol injections into the MLR produced two types of responses: either increased or decreased locomotion. Hypermotility resulted from microinjections of glutamate, and picrotoxin and bicuculline, into the ZI. The short latency, short duration response to glutamate resulted in a greater increase in locomotion than with picrotoxin or bicuculline when each was administered into the SLR. These results provide further evidence for the functional role of the MLR and SLR in the initiation of locomotor activity in the intact, freely behaving rat.