Effects of chronic weight perturbation on energy homeostasis and brain structure in mice.

Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (-10-15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.

Hypercalcitoninemia in a patient with a recurrent goitre and insulinoma: a case report.

Serum calcitonin has become a very sensitive and specific marker for medullary thyroid carcinoma that should be determined in patients with nodular thyroid disease. However, a few earlier reports indicated that tumors other than medullary thyroid carcinoma including insulinomas arising from pancreatic islet cells may also produce calcitonin. Of the few cases of calcitonin-producing insulinomas previously reported, most had incomplete data or lack of documentation of the association between raised serum calcitonin concentration and immunohistochemical detection of calcitonin in pancreatic islet cell tumors. In this paper we are reporting a 54-year-old woman with a history of partial thyroidectomy for multinodular goitre at the age of 50 yrs, she was evaluated for a 2-months history of fasting hypoglycemia (plasma glucose 1.9 mmol/L during a supervised fast), raised serum insulin (at the time of hypoglycemia 88.8 microU/ml; normal, 5 - 35 microU/ml) and C-peptide levels (at the time of hypoglycemia 6.1 ng/ml; normal, 1.37 - 3.51 ng/ml), markedly increased serum calcitonin concentration (481 pg/ml; normal, < 9.9 pg/ml), and an enlarged residual thyroid gland. Aspiration biopsy of the thyroid was negative for parafollicular C-cell hyperplasia or medullary thyroid carcinoma. Abdominal ultrasound and CT scan revealed a tumor in the head of the pancreas, which was surgically removed. Histopathological evaluation of the pancreatic tumor showed typical features of a neuroendocrine neoplasm with strong immunostaining for both insulin and calcitonin. After removal of the pancreatic tumor, clinical symptoms resolved and biochemical markers normalized (serum insulin, 14.9 microU/ml; C-peptide, 3.0 ng/ml; calcitonin, 2.9 pg/ml) confirming the causal relationship between insulinoma and markedly increased serum calcitonin levels.

Endothelial nitric oxide in diabetes mellitus: too much or not enough?

Vascular complications are the leading cause of increased mortality in patients with diabetes mellitus. Endothelial dysfunction, characterised by impaired endothelium-dependent vasoreactivity, is the first sign of blood vessel damage that precedes morphological changes of the vessel wall. With other factors altered bioavailability of nitric oxide, the most potent endothelium-derived vasodilator, contributes to the changes in vascular tone and integrity. In addition to the impairment of vascular reactivity and permeability, other anti-atherosclerotic functions of nitric oxide are also diminished, which may result in activated monocyte, leukocyte and platelet adhesion to the endothelium, increased platelet aggregation, lipoprotein influx to the subendothelial space and smooth muscle proliferation. Hyperglycaemia-induced increased oxidative stress and impairment of antioxidant defence are suggested to play a role in the pathomechanism of vascular damage, partly by influencing nitric oxide. Both in experimental and clinical Type 1 and Type 2 diabetes mellitus the apparently conflicting data of increased, unaltered or diminished nitric oxide action suggests a complex, time and localisation-dependent alteration of vascular function. The understanding of the mechanisms that lead to diabetic endothelial dysfunction and its early detection are necessary to establish appropriate intervention to prevent irreversible atherosclerotic vessel damage in patients with diabetes mellitus.

Circulating plasma endothelin-1, plasma lipids and complications in Type 1 diabetes mellitus.

UNLABELLED: The damage of endothelial integrity is an important step in the atherogenic process. To evaluate the role of circulating endothelin-1 (ET-1) in Type 1 diabetes mellitus (T1DM), plasma ET-1 levels were evaluated in T1DM patients either with (n=9) or without hyperlipidaemia (n=11), or with (n=9) and without (n=11) late diabetic complications, in non-diabetic hyperlipidaemic patients (n=17) and in healthy volunteers. Groups were matched for age, sex and body mass index. RESULTS: Serum total cholesterol and apolipoprotein B were significantly higher in the diabetic group (p<0.05). Plasma ET-1 level was similar in controls and in non-diabetic hyperlipidaemic subjects (5.77+/-1.74 ng/l vs 4.97+/-1.58 ng/l); however, diabetic hyperlipidaemic patients had a significantly higher plasma ET-1 concentration compared to control subjects (6.67+/-2.44 ng/l vs 4.97+/-1.58 ng/l, p<0.05). Diabetic patients with vascular complications had a significantly higher plasma ET-1 concentration than found in diabetic patients without complications (6.99+/-2.17 ng/l vs 4.74+/-1.27 ng/l, p<0.01) and in controls (6.99+/-2.17 ng/l vs 4.97+/ 1.58 ng/l, p<0.01). Patients with diabetic complications also had a significantly higher apolipoprotein B level compared to healthy controls (0.94+/-0.37 g/l vs 0.66+/-0.12 g/l, p<0.005). CONCLUSION: The susceptibility of T1DM patients to the development of atherosclerosis might be attributed to the relationship between elevated lipid levels and ET-1.

Role of endothelin-1 in diabetes mellitus.

Endothelin-1 is mainly synthesized by the vascular endothelial cells and acts on the vascular smooth muscle. Because of its vasoconstrictor and mitogenic effects it plays a role in the development of vascular diseases. In diabetes mellitus atherosclerosis is accelerated. The authors summarize the available data of the role of endothelin-1 in Type 1 and Type 2 diabetes mellitus and the development of diabetic complication.

[Endothelin-1 and its role in diabetes mellitus]. / Az endothelin-1 és szerepe diabetes mellitusban.

Endothelin-1 is mainly synthesised by the vascular endothelial cells and acts on the vascular smooth muscle. There are special endothelin receptors, endothelin receptor-A and endothelin receptor-B expressed on the vascular smooth muscle cells. Endothelin-1 through second messengers mobilises the intracellular calcium storage. The level of endothein-1 was found to be higher than normal in several diseases. Because of its vasoconstrictor and mitogenic effects it plays a role in the development of vascular diseases. The most severe and most frequent complications of diabetes mellitus are micro- and macroangiopathy. The authors summarise the physiological functions of endothelin-1 and its role in the development of diabetic angiopathy.