Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice.

AIMS/HYPOTHESIS: Modulation of central nervous system (CNS) and extra-CNS cannabinoid receptor type 1 (CB1R) affects metabolic conditions, independently of weight loss. Here we examined the relative contributions of acute CNS and extra-CNS CB1R modulation on insulin sensitivity using pharmacological gain- and loss-of-function of CB1R in mice. METHODS: We assessed the effects of acute modulation of CB1R on insulin sensitivity and tissue glucose uptake by administering a CB1R agonist (HU210) and antagonist (AM251) (vs vehicle) i.v. in wild-type mice. In addition, we administered a CB1R agonist (vs vehicle) systemically (i.v.) to Cb1r (also known as Cnr1) knockout (Cb1r (-/-)) mice or intracerebroventricularly (i.c.v.) in wild-type mice to elucidate the peripheral vs CNS-mediated regulatory effect of CB1R on insulin sensitivity. RESULTS: HU210 induced significant insulin resistance in wild-type mice with a reduction of whole-body glucose disappearance rate and muscle Akt phosphorylation, as well as of glucose uptake by skeletal muscle, but not by adipose tissue, changes that were prevented by pretreatment with AM251. HU210 did not affect insulin sensitivity in Cb1r (-/-) mice, suggesting that the observed effects were mediated through CB1R. HU210 administered i.c.v. did not induce insulin resistance, suggesting that acute stimulation of CNS CB1R was not required for this effect. CONCLUSIONS/INTERPRETATION: Skeletal muscle insulin sensitivity is affected by acute CB1R modulation. These changes are mediated by extra-CNS CB1R, probably by the receptors in skeletal muscle tissue.

Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men.

AIMS/HYPOTHESIS: Antioxidants have been shown to ameliorate lipid-induced impairment of insulin action and beta cell function, both in vitro and in animal studies. The aim of the present study was to examine the effects of two orally administered antioxidants, N-acetylcysteine (NAC) and taurine (TAU), on lipotoxicity in humans. METHODS: Nine non-diabetic men, who were either overweight or obese, underwent three studies each, 4-6 weeks apart, in random order: (1) i.v. infusion of saline for 48 h (SAL); (2) i.v. infusion of Intralipid and heparin for 48 h to mimic chronic elevation of plasma NEFA (IH); and (3) IH infusion for 48 h with concurrent oral NAC (IH+NAC). Six men underwent similar studies except for study 3, where instead of NAC they received a 2 week pretreatment with oral TAU (IH+TAU). RESULTS: For both the NAC and TAU studies, a 48 h IH infusion alone without antioxidant impaired insulin sensitivity (S(I), 63% and 62% of SAL in NAC and TAU studies, respectively) and beta cell function, as evidenced by a reduction in disposition index (DI, 55% and 54% of SAL in NAC and TAU studies, respectively). NAC failed to prevent the lipid-induced increase in levels of the plasma oxidative stress marker malondialdehyde and did not prevent the lipid-induced reduction in S(I) or DI, whereas TAU completely prevented the rise in malondialdehyde and decreased 4-hydroxynonenal, and significantly improved S(I) (91% of SAL) and DI (81% of SAL). CONCLUSIONS/INTERPRETATION: Oral TAU ameliorates lipid-induced functional beta cell decompensation and insulin resistance in humans, possibly by reducing oxidative stress.

Portal venous and enteric exocrine drainage versus systemic venous and bladder exocrine drainage of pancreas grafts: clinical outcome of 40 consecutive transplant recipients.

OBJECTIVE: To test the hypothesis that pancreas transplantation using the more physiologic method of portal venous-enteric (PE) drainage could be performed without compromising patient and graft outcome, compared with the standard method of systemic venous-bladder (SB) drainage. METHODS: Between November 1995 and November 1998, the authors prospectively followed up 20 consecutive patients with SB drainage followed by 20 consecutive patients with PE drainage. All patients underwent simultaneous pancreas-kidney transplantation, and all were immunosuppressed with antilymphocyte serum, cyclosporin, azathioprine, and steroids. RESULTS: The actuarial patient survival rate at 1 year was 95% in the SB group and 100% in the PE group. Death-censored kidney graft survival was 100% in both groups; pancreas graft survival was 95% in the SB group and 100% in the PE group. The mean initial hospital stay was 15 days for both groups. However, during the first 6 months after transplantation, the SB group required more medical day-unit visits, mostly for treatment of metabolic acidosis and dehydration. The incidence of urinary tract infections was similar in both groups. The incidence of cytomegalovirus infections was significantly less in the PE group. The incidence of acute rejection was 37% in the SB group and 15% in the PE group. Mean serum creatinine levels 6 months after transplantation were significantly lower in the PE group than in the SB group. Glycemic control was excellent in both groups, but fasting serum insulin levels were significantly lower in the PE group. CONCLUSIONS: The PE method of pancreas transplantation can be performed with excellent patient and graft outcomes.

Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels.

Polycystic ovarian syndrome (PCOS) is a common disorder associated with hyperandrogenemia and infertility. Abdominal obesity, insulin resistance, and dyslipoproteinemias are other common metabolic disorders typically found in women with PCOS. The cause-effect relationship between hyperandrogenemia and insulin resistance-dyslipoproteinemia remains unclear. In this study, we have investigated the changes in androgenemia, insulin sensitivity, and plasma lipid-lipoprotein levels after laparoscopic ovarian cautery (LOC) for ovulation induction in eight infertile women with clomiphene citrate-resistant PCOS. After LOC, significant decreases in androstenedione (43%), testosterone (48%), and free testosterone (48%) concentrations were observed (P < 0.05). Glucose utilization during an euglycemic-hyperinsulinemic clamp did not change after LOC. In addition, no significant changes after the surgical procedure were observed for cholesterol, triglycerides, and apolipoprotein concentrations measured in total plasma and in different lipoprotein fractions. In conclusion, within the short duration of observation of this study, our findings demonstrate that insulin resistance and lipoprotein abnormalities associated with PCOS are not secondary to hyperandrogenemia. The clinician, therefore, must be cognizant of the persistence of these metabolic risk factors for cardiovascular disease once successful ovulation and fertility is restored, and institute appropriate monitoring, counseling, and medical intervention as required.

Serum creatinine level is an independent risk factor for the angiographic severity of internal carotid artery stenosis in subjects who have previously had transient ischaemic attacks.

BACKGROUND: Serum creatinine level has been reported to be related to the incidence of strokes. OBJECTIVE: To examine the relationship between serum creatinine level and the severity of extracranial carotid artery atherosclerosis. DESIGN AND METHODS: This is a secondary analysis of data from 88 patients (59 men and 29 women) who had previously had transient ischaemic attacks or minor strokes and had been included in intervention trials of symptomatic carotid disease. Narrowing of internal carotid artery was estimated by angiography. Both internal carotid arteries were measured and the severity was expressed as the sum of percentage stenoses on both sides. The risk profiles of patients with moderate and severe internal carotid artery stenosis were compared. RESULTS: The sex-adjusted mean serum creatinine concentration in those with severe carotid disease was significantly higher than that in those with moderate disease (106.3 +/- 3.3 versus 91.3 +/- 3.7 mumol/l, P = 0.003), but still within the normal range. The risk of having severe disease was compared with risk of having moderate disease for people ranked by their serum creatinine levels. Univariate logistic regression showed that the odds ratio (OR) for having severe involvement of internal carotid artery was greater for patients in mid-tertile of creatinine values than it was for those in the lowest tertile (OR 6.3, 95% confidence interval 2.0-20.4, P = 0.002). The creatinine levels of patients in these two tertiles were within the normal range. The OR was no greater for patients in the highest tertile of creatinine values, which were slightly elevated above the normal range. These OR did not change after adjustment for age, sex, hypertension or systolic blood pressure, diabetes, smoking and lipid levels. CONCLUSION: Results of this study demonstrate for the first time that serum creatinine level, even within the range of upper normal or mildly elevated levels, is related to the angiographic severity of internal carotid artery disease in patients who have previously had transient ischaemic attacks and that this relationship is independent of classic cardiovascular risk factors.

Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state.

The role of hyperinsulinemia in the pathogenesis of triglyceride (TG) and VLDL over-production in insulin-resistant states remains controversial. While studies in humans and animals have generally suggested that chronic hyperinsulinemia facilitates VLDL production, particularly in the presence of an abundant supply of substrate for VLDL synthesis, the majority of in vitro studies using cultured hepatocytes and hepatoma cell lines have demonstrated an acute inhibitory effect of insulin. Using radiolabeled VLDL tracers we have examined the acute effect of hyperinsulinemia on VLDL production in humans. We found a rapid suppression of plasma free fatty acid (FFA) levels in response to insulin and a consistent 50-60% insulin-induced suppression of both VLDL TG and VLDL apolipoprotein (apo) B in lean insulin-sensitive individuals. Elevation of plasma FFA levels by infusing heparin and Intralipid without hyperinsulinemia resulted in a marked increase in VLDL TG and VLDL apoB production. When the insulin-induced suppression of plasma FFA levels was prevented during hyperinsulinemia, VLDL TG production was still inhibited, although to a lesser extent than with insulin alone. We concluded from these findings that insulin suppresses VLDL production in insulin-sensitive humans partly by suppressing plasma FFA levels and partly by a non-FFA-mediated (perhaps direct hepatic) mechanism. In addition, we found that chronically insulin-resistant hyperinsulinemic obese individuals were resistant to this suppressive effect of insulin on VLDL apoB production, in keeping with similar findings by others performing in vitro experiments using cultured hepatocytes isolated from insulin-resistant or hyperinsulinemic rats. The relevance of these findings to the mechanism of hypertriglyceridemia associated with chronic insulin-resistant states in humans remains a matter of speculation. One hypothesis is that resistance to the normal suppressive effect of insulin, in association with other metabolic abnormalities associated with insulin resistance, may contribute to postprandial and postabsorptive hypertriglyceridemia.

Diabetic dyslipidemia: a case for aggressive intervention in the absence of clinical trial and cost effectiveness data.

Patients with diabetes mellitus have a two- to fourfold increase in clinical manifestations of atherosclerotic cardiovascular disease (ASCVD). Traditional risk factors such as age, hypertension, left ventricular hypertrophy, hyperlipidemia and smoking are still operative in diabetes but do not account for the total increase in ASCVD risk associated with diabetes. The most common lipid abnormalities in noninsulin-dependent diabetes mellitus and poorly controlled insulin-dependent diabetes mellitus are hypertriglyceridemia and low high density lipoprotein cholesterol. Evidence is presented to support the hypothesis that these lipid abnormalities are atherogenic in diabetes. Treatment of diabetic dyslipidemia with conservative measures (diet, weight loss, aerobic exercise, improved glycemic control) and pharmacological management have been shown to be highly effective in normalizing the lipid abnormalities. However, few trials of lipid lowering therapy have included patients with known diabetes mellitus and, to date, there have been no well-controlled prospective trials of lipid lowering therapy in diabetes. There is therefore no definitive proof regarding the benefit of lipid lowering therapy in diabetes mellitus. There are also no data regarding the cost effectiveness of lipid lowering therapy in reducing ASCVD complications in diabetes. There are data, however, showing that complications of ASCVD in patients with diabetes account for a large percentage of total health care expenditures. The overwhelming evidence that patients with diabetes have a high rate of ASCVD, that traditional risk factors for ASCVD are operative in diabetes and that the dyslipidemia of diabetes is highly prevalent and proatherogenic, predicts that the treatment of ASVD risk factors, including dyslipidemia, will be associated with a substantial reduction in ASCVD complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression.

Subnormal free T4 index (FT4I) values (less than 80) with inappropriately normal serum TSH concentrations that could not be attributed to illness or drugs were found in 2.5% of ambulating elderly clinic patients. Six such individuals (three men and three women, aged 68.8 +/- 4.8 yr) were selected for their persistent thyroid test abnormalities and were sex and age matched to six subjects (67.7 +/- 4.9 yr) with normal FT4I (greater than 90) and TSH levels. The former also had low serum total T4 (TT4) and rT3 (TrT3) concentrations, but total T3 (TT3) and basal TSH values were normal and did not differ between the groups. Responses of ACTH, LH, FSH, TSH, and PRL to stimulation with CRH, GnRH, and TRH showed no differences between the two groups, indicating that the normal TSH concentration, inappropriate for the low FT4I level, is not due to generalized hypothalamic or pituitary dysfunction. Administration of 3 g iopanoic acid (IOP) daily for 3 days produced significant increases in the TT4 and TrT3 concentrations to the same degree in both groups. Also, in both groups the IOP-induced suppression of T4 to T3 conversion in the pituitary gland provoked similar increases in basal TSH (280 +/- 47% and 288 +/- 33%) and TSH secretion in response to TRH (173 +/- 7% and 156 +/- 13%). These results indicate that the low FT4I is not the consequence of reduced pituitary TSH reserve. In addition, evidence for normal thyroid gland reserve and the secretion of TSH of normal biological activity was obtained by comparing the acute iodothyronine responses to TRH-induced TSH release in both groups. It is concluded that the normal serum TSH concentration, inappropriate for the low FT4I value in some elderly subjects, is due to an apparent resetting of the thyroid hormone feedback regulation threshold of TSH secretion. It may, in turn, be the result of enhanced pituitary conversion of T4 to T3 or increased T4 uptake by the thyrotrophs.