Glucagon and Liver Fat are Downregulated in Response to Very Low-calorie Diet in Patients with Obesity and Type-2 Diabetes.

BACKGROUND AND STUDY AIMS: In patients with obesity and type-2 diabetes, short-time very low-calorie diet may ameliorate hyperglycemia and hepatic steatosis. Whether this also implies the glucose-regulating hormone glucagon remains to be elucidated. This study investigated the effects of a very low-calorie diet on plasma levels of glucagon and liver fat in obese patients with type-2 diabetes. PATIENTS AND METHODS: Ten obese patients with type-2 diabetes, 6 men and 4 women, were included. At baseline, fasting plasma glucagon, insulin and glucose were determined, and liver fat and stiffness evaluated by transient elastography. The subjects were then prescribed a very low-calorie diet of maximum 800 kcal/day for 7 weeks and reexamined after 7 weeks and 12 months. RESULTS: At baseline, BMI was 42±4 kg/m2 and fasting glucose 10.6±3.4 mmol/l. All patients had hepatic steatosis. Plasma glucagon was strongly related to liver fat (r2=0.52, p=0.018). After 7 weeks of very low-calorie diet, plasma glucagon was significantly decreased by nearly 30% (p=0.004) along with reductions of BMI (p<0.0001), glucose (p=0.02), insulin (p=0.03), liver fat (p=0.007) and liver stiffness (p=0.05). At 12 months follow-up, both glucagon and liver fat increased and were not different to basal levels, despite persistent reductions of BMI (p<0.002) and glucose (p=0.008). CONCLUSION: In obese type-2 diabetic subjects, plasma glucagon and liver fat are correlated and similarly affected by a very low-calorie diet, supporting a role of hepatic steatosis in glucagon metabolism.

Omentectomy in Addition to Bariatric Surgery-a 5-Year Follow-up.

AIM: Omentectomy in addition to bariatric surgery has been suggested to improve metabolic outcome but short-term (6-24 months) studies have refuted this notion. We investigated whether there was any long-term impact of omentectomy. METHODS: Forty-nine obese women underwent gastric bypass surgery and were randomly assigned to omentectomy (n = 26) or not (n = 23). They were re-examined after 5 years including dual-energy X-ray absorptiometry for body composition, blood pressure and blood sampling. RESULTS: There were no significant differences between the two groups at baseline (p = 0.07-0.93) or 5 years post-operatively (p = 0.15-0.93) regarding weight, BMI, body composition, HOMA-IR, plasma cholesterol, HDL cholesterol, or triglycerides. CONCLUSION: In agreement with previous shorter studies, removal of the greater omentum in addition to GBP is not associated with metabolic benefits after long-term follow-up.

Diabetes Mellitus Is Associated With Reduced High-Density Lipoprotein Sphingosine-1-Phosphate Content and Impaired High-Density Lipoprotein Cardiac Cell Protection.

OBJECTIVE: The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect. APPROACH AND RESULTS: We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabetic patients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (P<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (P<0.001) and the levels of hemoglobin A1c in diabetic patients (P<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (P<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (P<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function. CONCLUSIONS: Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature.

[Skin lightening products are a part of everyday life in many parts of the world. Corticosteroids, hydroquinone and mercury are common ingredients]. / Hudblekningsprodukter en del av vardagen i stora delar av världen - Kortikosteroider, hydrokinon och kvicksilver vanliga ingredienser.

During the past decade, attention has been drawn towards the globally increased usage of skin-lightening (bleaching) products which are manufactured and sold, particularly in Africa and Asia, but also via the internet and in local shops all over North America and Europe. The active ingredients include hydroquinone, mercury and potent corticosteroids which can have severe health effects.  After investigating a patient at our clinic where the symptoms and findings could be linked to the use of bleaching products, we started to search the literature for similar cases. We found a global epidemic of health disorders related to skin lightening products. With this article we want to increase the awareness among Swedish physicians of this growing and harmful cosmetic trend.

Changes in subcutaneous fat cell volume and insulin sensitivity after weight loss.

OBJECTIVE: Large subcutaneous fat cells associate with insulin resistance and high risk of developing type 2 diabetes. We investigated if changes in fat cell volume and fat mass correlate with improvements in the metabolic risk profile after bariatric surgery in obese patients. RESEARCH DESIGN AND METHODS: Fat cell volume and number were measured in abdominal subcutaneous adipose tissue in 62 obese women before and 2 years after Roux-en-Y gastric bypass (RYGB). Regional body fat mass by dual-energy X-ray absorptiometry; insulin sensitivity by hyperinsulinemic-euglycemic clamp; and plasma glucose, insulin, and lipid profile were assessed. RESULTS: RYGB decreased body weight by 33%, which was accompanied by decreased adipocyte volume but not number. Fat mass in the measured regions decreased and all metabolic parameters were improved after RYGB (P < 0.0001). Whereas reduced subcutaneous fat cell size correlated strongly with improved insulin sensitivity (P = 0.0057), regional changes in fat mass did not, except for a weak correlation between changes in visceral fat mass and insulin sensitivity and triglycerides. The curve-linear relationship between fat cell size and fat mass was altered after weight loss (P = 0.03). CONCLUSIONS: After bariatric surgery in obese women, a reduction in subcutaneous fat cell volume associates more strongly with improvement of insulin sensitivity than fat mass reduction per se. An altered relationship between adipocyte size and fat mass may be important for improving insulin sensitivity after weight loss. Fat cell size reduction could constitute a target to improve insulin sensitivity.

Omentectomy in addition to gastric bypass surgery and influence on insulin sensitivity: a randomized double blind controlled trial.

BACKGROUND & AIMS: Accumulation of visceral adipose tissue is associated with insulin resistance and cardio-vascular disease. The aim of this study was to elucidate whether removal of a large amount of visceral fat by omentectomy in conjunction with Roux en-Y gastric bypass operation (RYGB) results in enhanced improvement of insulin sensitivity compared to gastric bypass surgery alone. METHODS: Eighty-one obese women scheduled for RYGB were included in the study. They were randomized to RYGB or RYGB in conjunction with omentectomy. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp before operation and sixty-two women were also reexamined 2 years post-operatively. The primary outcome measure was insulin sensitivity and secondary outcome measures included cardio-metabolic risk factors. RESULTS: Two-year weight loss was profound but unaffected by omentectomy. Before intervention, there were no clinical or metabolic differences between the two groups. The difference in primary outcome measure, insulin sensitivity, was not significant between the non-omentectomy (6.7 ± 1.6 mg/kg body weight/minute) and omentectomy groups (6.6 ± 1.5 mg/kg body weight/minute) after 2 years. Nor did any of the cardio-metabolic risk factors that were secondary outcome measures differ significantly. CONCLUSION: Addition of omentectomy to gastric bypass operation does not give an incremental effect on long term insulin sensitivity or cardio-metabolic risk factors. The clinical usefulness of omentectomy in addition to gastric bypass operation is highly questionable. CLINICAL TRIAL REGISTRATION NUMBER: NCT01785134.

Increased visceral adipocyte lipolysis--a pathogenic role in nonalcoholic fatty liver disease?

CONTEXT: Obesity is a major risk factor for nonalcoholic fatty liver disease, but the primary pathophysiological mechanisms remain unclear. OBJECTIVE: The aim was to study the relative role of visceral and sc in vitro lipolysis for liver fat accumulation. PATIENTS: Eighteen morbidly obese women participated in the study. DESIGN: Hepatic triglyceride accumulation and abdominal visceral and sc fat area were assessed by computer tomography. Biopsies were taken from abdominal sc and visceral fat tissue. Basal and maximal lipolysis was measured using various lipolytic drugs acting at different steps in the lipolytic cascade. RESULTS: No difference in total body, visceral, or sc fat mass was found between patients with high, intermediate, or low amounts of liver fat. In patients with high liver fat content, there was an approximately 2-fold increase in visceral adipocyte maximal glycerol release induced by the different lipolytic agents (P = 0.002 to 0.01). Noradrenaline-mediated free fatty acid release from visceral adipocytes was also about twice as high in patients with high liver fat (P = 0.004). In contrast, in sc adipocytes, no relationship between liver fat content and either glycerol or free fatty acid release was found. CONCLUSIONS: We suggest a pathogenic role of visceral, but not sc, adipocyte lipolytic function in nonalcoholic fatty liver disease, independent of total body fat as well as abdominal fat distribution.

Human adipose tissue cannabinoid receptor 1 gene expression is not related to fat cell function or adiponectin level.

CONTEXT: The cannabinoid receptor 1 gene (CNR1) is implicated in adipocyte function. OBJECTIVE: We investigated human adipose tissue CNR1 mRNA in relation to obesity, clinical and metabolic variables, adipocyte function, and adiponectin (ADIPOQ) levels. METHODS: We assessed sc fat biopsies from 96 obese and nonobese subjects and omental fat biopsies from 82 obese and nonobese subjects. RESULTS: The sc and omental adipose CNR1 gene expression were similar in obese and nonobese subjects. No association between either sc or omental adipose CNR1 mRNA levels and body mass index, waist circumference, plasma levels of glucose and insulin, lipids, or blood pressure was found. The sc and omental maximal adrenergic lipolytic activation as well as lipolytic adrenoceptor sensitivity were not related to CNR1 gene expression. Lipogenesis in sc adipocytes also showed no association with CNR1 mRNA levels. Finally, no relation was found between adipose CNR1 gene expression and ADIPOQ mRNA, adipose tissue adiponectin secretion, or circulating adiponectin. CONCLUSION: We found no association of human adipose tissue CNR1 mRNA expression with measures of body fat, metabolic parameters, fat cell function, or ADIPOQ expression. These data do not suggest a major role of human adipose CNR1 in fat cell function or metabolic disease development.

Long-term prospective and controlled studies demonstrate adipose tissue hypercellularity and relative leptin deficiency in the postobese state.

CONTEXT: Enlarged fat cells and leptin hypersecretion are hallmarks of common obesity. OBJECTIVE: The objective of this study was to investigate fat cell size and leptin production in the basal state after long-term steady-state weight reduction to the nonobese state. DESIGN: This prospective case-control study had a duration of 3 +/- 1 (mean +/- sd) yr. PATIENTS: Twenty-five obese women (cases) were studied. Each case was compared with a control subject matched for age, sex, and body mass index (BMI) at nadir of weight for the cases. SETTING: This study was conducted at Karolinska University Hospital (Stockholm, Sweden). INTERVENTION: The subjects were followed until they reached a steady-state weight reduction after lifestyle modification or bariatric surgery (cases). Treatment target was the nonobese state (BMI < 30 kg/m2). Subcutaneous adipose tissue secretion of leptin, serum leptin levels, and fat cell volume were determined after an overnight fast. RESULTS: Ten obese women (40%) reached the nonobese state. This was accompanied by marked decreases in fat cell volume, leptin secretion, and serum leptin concentrations (P < 0.0001). The postobese cases had 43% smaller fat cell volume (P = 0.0008), 68% lower adipocyte leptin production (P = 0.001), and 54% lower serum leptin levels (P = 0.0007) than control subjects, despite almost identical percent body fat in the two groups. Fat cell volume, but not percent body fat or BMI, was directly proportional to leptin secretion and serum leptin concentrations. CONCLUSION: Adipose tissue hyperplasia (too many small fat cells) and low leptin production resulting in relative hypoleptinemia in the fasting (basal) state are common features of the postobese state in women.

Major gender differences in the lipolytic capacity of abdominal subcutaneous fat cells in obesity observed before and after long-term weight reduction.

The influence of obesity on the lipolytic capacity of isolated sc fat cells was studied prospectively in 13 women and 10 men, all obese, but otherwise healthy, before and 2 and 3 yr after weight reduction by bariatric surgery. Nonobese subjects (25 women and 17 men) without a family history of obesity served as the control group. Lipolytic capacity was determined after stimulation at different steps of the lipolytic cascade with noradrenaline, isoprenaline, forskolin, and (Bu)(2)AMP. Bariatric surgery was followed by a marked and similar reduction of body mass index and fat cell volume (approximately 40%) in both genders. Before weight loss, lipolytic capacity per cell was elevated in obese women and decreased to normal levels after weight reduction at 2 and 3 yr. However, lipolytic capacity per fat cell surface area was not changed in obese women. In obese men, lipolytic capacity per cell was almost the same as in lean men and was not influenced by weight reduction. Lipolytic capacity was related to fat cell size in women (P = 0.0008; r = 0.58), but not in men (P = 0.67; r = 0.086). The protein content of hormone-sensitive lipase, which determines lipolytic capacity, was significantly lower in obese men and women and increased slightly after weight reduction in men only. Thus, in women, but not in men, the adipocyte lipolytic capacity is influenced by obesity and weight reduction, probably due to changes in fat cell size. These gender differences are not related to the amount of hormone-sensitive lipase protein in adipocytes.