Biliopancreatic Diversion as a Novel Approach to the HAIR-AN Syndrome

Background. The HAIR-AN syndrome is a rare multisystem disorder in women, that consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The IR is likely due to a primary defect of the insulin receptor. Methods: We report the case of a 42-year-old Caucasian woman with HAIR-AN syndrome, impaired glucose tolerance (IGT), mild hyperlipemia, and hypertension, who underwent biliopancreatic diversion (BPD). Results: Within 24 months follow-up after BPD, impaired glucose tolerance, mild hyperlipemia, and hypertension completely reversed. Although insulin sensitivity, estimated by the euglycemic hyperinsulinemic clamp, did not improve, signs and symptoms of hyperandrogenism and acanthosis nigricans resolved fully. Conclusion: In HAIR-AN syndrome, malabsorptive bariatric surgery is effective in improving hyperandrogenism and acanthosis nigricans, with noteworthy esthetic consequences. BPD was followed by disappearance of co-morbidities of the syndrome, such as IGT, hypertension and hyperlipemia.     

The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes

SUMMARY BACKGROUND DATA: Most patients who undergo Roux-en-Y gastric bypass (RYGB) experience rapid resolution of type 2 diabetes. Prior studies indicate that this results from more than gastric restriction and weight loss, implicating the rearranged intestine as a primary mediator. It is unclear, however, if diabetes improves because of enhanced delivery of nutrients to the distal intestine and increased secretion of hindgut signals that improve glucose homeostasis, or because of altered signals from the excluded segment of proximal intestine. We sought to distinguish between these two mechanisms. METHODS: Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach-preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restored in rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrient absorption were measured. RESULTS: There were no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated rats had markedly better oral glucose tolerance compared with all control groups as shown by lower peak and area-under-the-curve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrient passage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passage in DJB rats reestablished impaired glucose tolerance. CONCLUSIONS: This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes.     

The role of sonoelastography in the differential diagnosis of neck nodules

Sonoelastography is an imaging technique that provides information on tissue elasticity. Its use as a diagnostic procedure is based on the premise that pathological processes like cancer alter the physical characteristics of the involved tissue. Ultrasonographic studies of the neck can reveal the nonpalpable thyroid nodules, but the nature of these lesions generally has to be established on the basis of FNAB findings. In our hands, sonoelastography displayed a diagnostic accuracy of 86.2% in identifying thyroid nodule malignancy, with positive and negative predictive values (PPV and NPV) of 64% and 94.5%, respectively. In the study of cervical lymph nodes, the results were less impressive (sensitivity 75%, specificity 80%, accuracy 77%, PPV 80%, NPV 70%), but the information obtained with this technique can in our opinion be a useful adjunct to sonographic findings. Indeed, in 5 lymph nodes with sonographic features consistent with malignancy, sonoelastography revealed diffuse elasticity that was indicative of benign disease, which was confirmed by pathological studies. Other nodular lesions of the neck can also be evaluated with sonoelastography, including enlarged parotid glands, but the data in the literature are too limited to allow hypotheses on the role of this imaging modality in this field. Sonoelastography is rapid and simple to perform, and it appears to be a potentially useful tool for the differential diagnosis of neck nodules. This is particularly true of thyroid nodules. Our experience with these lesions indicates that diffuse elasticity is strongly correlated with benign disease. If this finding is confirmed in larger studies, sonoelastography might be used to identify thyroid nodules that do not require immediate biopsy.     

Body weight, not insulin sensitivity or secretion, may predict spontaneous weight changes in nondiabetic and prediabetic subjects: the RISC study

OBJECTIVE

Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes.

RESEARCH DESIGN AND METHODS

In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19–44 kg/m², 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and β-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose).

RESULTS

Insulin sensitivity was similar in weight gainers (top 20% of the distribution of BMI changes), weight losers (bottom 20%), and weight stable subjects across quartiles of baseline BMI. By multiple logistic or linear regression analyses controlling for center, age, sex, and baseline BMI, neither insulin sensitivity nor any β-cell function parameter showed an independent association with weight gain; this was true in normal glucose tolerance, impaired glucose tolerance, and whether subjects progressed to dysglycemia or not. Baseline BMI was significantly higher in gainers (26.1 ± 4.1 kg/m²) and losers (26.6 ± 3.7 kg/m²) than in weight stable subjects (24.8 ± 3.8 kg/m², P < 0.0001 for both gainers and losers). Baseline waist circumference (or equivalently, BMI or weight) was a positive, independent predictor of both weight gain and weight loss (odds ratio 1.48 [95% CI 1.12–1.97]) in men and (1.67 [1.28–2.12]) in women. In men only, better insulin sensitivity was an additional independent predictor of weight loss.

CONCLUSIONS

Neither insulin sensitivity nor insulin secretion predicts spontaneous weight gain. Individuals who have attained a higher weight are prone to either gaining or losing weight regardless of their glucose tolerance.The epidemic of obesity and the attendant increased risk of diabetes and cardiovascular disease pose a demand for devising and implementing strategies to combat and/or prevent obesity. Although much work has addressed the metabolic consequences of weight gain, relatively few studies have focused on the metabolic predictors of weight change. Because insulin resistance is, like obesity, a major risk factor for the development of diabetes, it is of special interest to establish the relation of insulin resistance to body weight changes. Several reports have examined the relationship between insulin action and weight gain (1) found that insulin sensitivity, not insulin resistance, predicted spontaneous weight gain. Likewise, in a small clinical study in women (5), clamp-based insulin sensitivity predicted weight regain after initial weight loss. Other studies using a variety of surrogate indices of insulin sensitivity in larger groups of individuals, however, have yielded mixed results, with roughly half of them reporting an association between insulin sensitivity and weight gain and the other half a relation of insulin resistance to subsequent weight gain. With regard to insulin secretion, again, the findings from studies using a host of proxies for β-cell function have been inconclusive (

A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: an elusive phenotype and a difficult diagnosis

Mutations in the A1 domain of von Willebrand factor (VWF) may be associated with gain of function in the VWF-platelet GPIb interaction and consumption of large VWF multimers, as seen in type 2B von Willebrand disease (VWD). We report a new VWF abnormality associated with greater VWF-GPIb interaction in the presence of all VWF multimers. The index case is a woman with a lifelong history of bleeding, found hyperresponsive to ristocetin with spontaneous platelet aggregation (SPA). She had normal factor VIII, VWF:Ag, VWF:RCo and VWF:CB levels, normal VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios, and a full panel of plasma and platelet VWF multimers. A missense mutation (4115T>G) was found in exon 28 of the VWF gene, which replaced a isoleucine with a serine at position 1372 of pre-pro-VWF (I1372S) at heterozygous level. Recombinant VWF carrying the I1372S mutation and showing a normal VWF multimer organisation was capable of inducing SPA on normal platelet-rich plasma (unlike wild-type VWF), as well as a hyper-response to ristocetin in the same platelets (0.6 mg/ml ristocetin vs. 1.2 of wild-type VWF). The new I1372S VWF mutation, characterized by SPA and hyper-responsiveness to ristocetin thus has some of the features of type 2B VWD, but not the lack of large VWF multimers, so we defined this variant as type 2B-like VWD. Why I1372S VWF is associated with bleeding symptoms, despite normal VWF levels and multimer organisation, remains to be seen.     

Influence of maternal obesity on insulin sensitivity and secretion in offspring

OBJECTIVE—The purpose of this study was to clarify the effects of maternal obesity on insulin sensitivity and secretion in offspring.RESEARCH DESIGN AND METHODS—Fifty-one offspring of both sexes of obese (Ob group) and 15 offspring of normal-weight (control group) mothers were studied. Plasma glucose, insulin, and C-peptide were measured during an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated using the oral glucose insulin sensitivity index, and insulin secretion and β-cell glucose sensitivity were computed by a mathematical model. Fasting leptin and adiponectin were also measured. Body composition was assessed by dual-X-ray absorptiometry.RESULTS—No birth weight statistical difference was observed in the two groups. Of the Ob group, 69% were obese and 19% were overweight. The Ob group were more insulin resistant than the control group (398.58 ± 79.32 vs. 513.81 ± 70.70 ml⁻¹ · min⁻¹ · m⁻² in women, P < 0.0001; 416.42 ± 76.17 vs. 484.242 ± 45.76 ml⁻¹ · min⁻¹ · m⁻² in men, P < 0.05). Insulin secretion after OGTT was higher in Ob group than in control group men (63.94 ± 21.20 vs. 35.71 ± 10.02 nmol · m⁻², P < 0.01) but did not differ significantly in women. β-Cell glucose sensitivity was not statistically different between groups. A multivariate analysis of variance showed that maternal obesity and offspring sex concurred together with BMI and β-cell glucose sensitivity to determine the differences in insulin sensitivity and secretion observed in offspring.CONCLUSIONS—Obese mothers can give birth to normal birth weight babies who later develop obesity and insulin resistance. The maternal genetic/epigenetic transmission shows a clear sexual dimorphism, with male offspring having a higher value of insulin sensitivity (although not statistically significant) associated with significantly higher insulin secretion than female offspring.Type 2 diabetes is spreading out among young people as the incidence of obesity is increasing over time. This evidence has induced the American Diabetes Association (1) to include into the new classification recommendations of diabetes a form of type 2 diabetes with pubertal onset, variable insulin secretion, and decreased insulin sensitivity, strongly associated with obesity, which includes 10–20% of all diabetes in childhood and youth.Scientists have provided a pathophysiological explanation of this phenomenon by suggesting that the development of type 2 diabetes in youth reflects the combination of insulin resistance and relative insulin deficiency. However, the limited β-cell capacity is regarded as being of “little significance” (2) in the absence of obesity.Familial aggregation of BMI is well established in the medical literature. In a Swedish study on monozygotic twins reared in different familial contexts, within-pair correlations for BMI were 70% for men and 66% for women; these figures were quite similar for twins reared together, suggesting that familial environment did not play a relevant role in BMI in identical twins (3). Similar values for correlation coefficients (75%) were also found in a U.S. population of monozygotic twins (4).However, epigenetics also seems to contribute, together with genetic predisposition, to the development of obesity. Studies of inheritance unequivocally show that BMI of children correlates more closely with maternal than with paternal BMI, suggesting that in addition to the genetic influences, the in utero environment may contribute to the development of obesity in offspring. In fact, overweight/obese women are more likely to give birth to heavier babies (>90th centile) than normal-weight mothers (5). Studies of inheritance clearly demonstrated a stricter correlation between a child''s BMI and maternal rather than paternal BMI, suggesting that the in utero environment may contribute to the development of obesity in offspring (6,7). Gillman et al. (8) found that maternal BMI was an influencing variable in association with gestational diabetes and offspring obesity. Furthermore, Khan et al. (9–11) demonstrated that the consumption of a diet rich in saturated fat starting before conception and continuing through weaning led to increased hyperinsulinemia, adiposity, hypertension, and endothelial dysfunction in offspring at 6 months of age. Very recently, Shankar et al. (5) demonstrated that, at least in rats, maternal overweight at conception contributes to offspring obesity and insulin resistance and that programming of obesity occurs in the absence of changes in birth weights.However, at least to our best knowledge, there is only one study (12) in the literature that investigated insulin sensitivity but not insulin secretion in young lean offspring of obese parents compared with offspring of normal-weight parents. This study (12) failed to demonstrate any significant difference between groups.Our center follows obese subjects almost exclusively, and morbidly obese individuals represent >50% of the outpatient population. Recently, we have started to systematically study insulin sensitivity and insulin secretion in the offspring of obese and morbidly obese patients, after the observation that some of the young individuals with at least one parent, usually the mother, affected by obesity had impaired glucose tolerance (IGT) and/or hypertension independent of their body weight. In the present investigation insulin sensitivity, insulin secretion, and body composition were studied in offspring with a different maternal phenotype, namely normal weight or obesity.     

Effect of massive weight loss on inflammatory adipocytokines and the innate immune system in morbidly obese women

CONTEXT: Obesity may be regarded as a low-grade inflammatory state. OBJECTIVE: The aim of this study was to evaluate changes in pro-inflammatory adipocytokines and the innate immune system, cardiovascular risk, and insulin sensitivity after massive weight loss. DESIGN: This was a longitudinal study. Setting: The study was conducted at Catholic University, Rome. SUBJECTS AND METHODS: There were 10 normoglucose-tolerant obese women evaluated before and 36 months after bilio-pancreatic diversion (BPD). Glucose sensitivity (M value) was estimated using the euglycemic-hyperinsulinemic clamp. Mannan-binding lectin (MBL), bactericidal/permeability increasing protein (BPI), alpha-defensins, soluble CD14 receptor (sCD14), C-reactive protein, adiponectin, leptin, visfatin, IL-6, and TNF-alpha were assayed. RESULTS: After massive weight loss (53% of excess body weight), leptin (P 相似文献   

Thyroid Function and Insulin Sensitivity Before and After Bilio-pancreatic Diversion

Background  

Bilio-pancreatic diversion (BPD) induces permanent weight loss in previously severe obese patients through a malabsorptive mechanism. The aim of the study was to evaluate the modifications of circulating thyroid hormones after BPD, a surgical procedure which interferes with the entero-hepatic circulation of biliary metabolites.