Eva Ruzicska

Ghrelin: A new peptide regulating the neurohormonal system, energy homeostasis and glucose metabolism

Identification of ghrelin started with the discovery of growth hormone secretagogues, continued with the description of ghrelin receptors and ended with the elucidation of the chemical structure of ghrelin. However, several issues concerning the role of ghrelin in physiological and pathophysiological processes are still under investigation. Most of the ghrelin produced in the body is secreted in the stomach, but it is also expressed in the hypothalamus, pituitary, pancreas, intestine, kidney, heart and gonads. Ghrelin stimulates growth hormone secretion via growth hormone secretagogue receptors. Ghrelin secretion in the stomach depends on both acute and chronic changes in nutritional status and energy balance. Current data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion but, via ghrelin production, it also sends orexigenic (appetite increasing) signals to hypothalamic nuclei involved in the regulation of energy homeostasis. In addition to these main effects, ghrelin influences insulin secretion and glucose metabolism and it may exert potentially important effects on cardiovascular and gastrointestinal functions. Because of its effects on a large number of physiological functions, ghrelin may be involved in the pathomechanism of several human disorders, including disturbances of appetite, energy homeostasis and glucose metabolism. Further research might lead to a better understanding of the pathophysiology of ghrelin and might provide more effective therapy for the above disorders. Copyright

Na+,K+‐ATPase is modulated by angiotensin II in diabetic rat kidney – another reason for diabetic nephropathy?

Angiotensin II (ANGII) plays a central role in the enhanced sodium reabsorption in early type 1 diabetes in man and in streptozotocin‐induced (STZ) diabetic rats. This study investigates the effect of untreated STZ‐diabetes leading to diabetic nephropathy in combination with ANGII treatment, on the abundance and localization of the renal Na+,K+‐ATPase (NKA), a major contributor of renal sodium handling. After 7 weeks of STZ‐diabetes (i.v. 65 mg kg−1) a subgroup of control (C) and diabetic (D7) Wistar rats were treated with ANGII (s.c. minipump 33 μg kg−1 h−1 for 24 h; CA and D7A). We measured renal function and mRNA expression, protein level, Serin23 phosphorylation, subcellular distribution, and enzyme activity of NKA α‐1 subunit in the kidney cortex. Diabetes increased serum creatinine and urea nitrogen levels (C versus D7), as did ANGII (C versus CA, D7 versus D7A). Both diabetes (C versus D7) and ANGII increased NKA α‐1 protein level and enzyme activity (C versus CA, D7 versus D7A). Furthermore, the combination led to an additive increase (D7 versus D7A, CA versus D7A). NKA α‐1 Ser23 phosphorylation was higher both in D7 and ANGII‐treated rats in the non‐cytoskeletal fraction, while no signal was detected in the cytoskeletal fraction. Control kidneys showed NKA α‐1 immunopositivity on the basolateral membrane of proximal tubular cells, while both D7 and ANGII broadened NKA immunopositivity towards the cytoplasm. Our study demonstrates that diabetes mellitus (DM) increases the mRNA expression, protein level, Ser23 phosphorylation and enzyme activity of renal NKA, which is further elevated by ANGII. Despite an increase in total NKA quantity in diabetic nephropathy, the redistribution to the cystosol suggests the Na+ pump is no longer functional. ANGII also caused translocation from the basolateral membrane, thus in diabetic states where ANGII level is acutely elevated, the loss of NKA will be exacerbated. This provides another mechanism by which ANGII blockade is likely to be protective.

Cardiac gene expression of natriuretic substances is altered in streptozotocin-induced diabetes during angiotensin II-induced pressure overload

Objective To gain insight into the cardiac adaptive mechanisms in diabetes, we studied whether angiotensin II (Ang II) alters expression of the atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and adrenomedullin (AM) genes in the left ventricle of the diabetic rat heart. Methods Diabetes was induced by streptozotocin (STZ; 60 mg/kg body weight intravenously). During the last 24 h of 2.5 or 7 weeks of treatment of male Wistar rats with STZ or vehicle, Ang II (33 μg/kg per h) was administered via osmotic minipumps. Results Diabetes was associated with an increased left ventricular weight to body weight (LV/BW) ratio, an index of left ventricular hypertrophy, at week 7 but not at week 2.5, and with increased ANP mRNA content at 2.5 weeks, but not with altered expression of the AM and BNP genes. Mean arterial pressure and LV/BW ratio were increased by Ang II in all groups except in the 7-week diabetic group. Levels of ANP mRNA were increased fourfold (P < 0.001) and threefold (P < 0.05) by Ang II at 2.5 and 7 weeks in control animals, respectively, and 11-fold (P < 0.001) and sevenfold (P < 0.001) at 2.5 and 7 weeks in diabetic animals, respectively. Ang II increased ventricular concentrations of BNP mRNA in control and diabetic animals at 2.5 weeks (1.3-fold, P < 0.001; and 1.6-fold, P < 0.001) and at 7 weeks (1.3-fold, P < 0.05; and 1.8-fold, P < 0.001), respectively. Left ventricular levels of adrenomedullin mRNA were increased by treatment with Ang II for 24 h in 2.5-week diabetic animals. Conclusion. Ang II markedly increased the levels of natriuretic peptide mRNAs in the left ventricle of normal and diabetic rat hearts, whereas it increased adrenomedullin mRNA levels only in 2.5-week diabetic rats and failed to cause hypertension in 7-week diabetic rats. Left ventricular levels of ANP and BNP mRNA were increased by Ang II in diabetic animals more than the additive effects of diabetes and Ang II alone, showing that Ang II induced an amplified response with respect to cardiac concentrations of ANP and BNP in diabetes.

Adrenomedullin and diabetes mellitus

Adrenomedullin (AM) is a novel 52 amino acid peptide hormone, originally isolated from human pheochromocytoma. AM acts as a local autocrine and/or paracrine vasoactive hormone and has vasodilator and blood pressure lowering properties. AM as a vasodilative molecule protects the vascular wall but its exact role is still uncertain. AM is considered to play an important endocrine role in various tissues in maintaining electrolyte and fluid homeostasis. Its plasma concentration in healthy conditions is low. In hypertension, chronic renal failure and congestive heart failure its plasma concentration increases in a parallel manner with the severity of the disease. It is assumed that this peptide plays an important role in physiological and pathological conditions compensating the effects of vasoconstrictive molecules. Investigations have proven that in diabetic angiopathies the levels and production of vasoconstrictive factors and AM are increased, while other relaxing substances such as nitric oxide (NO) are decreased. It is still uncertain whether the increased release of AM is a compensatory mechanism or a coincidental event. Although the precise role of AM in the pathogenesis of diabetic complications is still to be elucidated, the altered concentration of AM in diabetes could indicate a certain interaction between AM induction and vascular function. Hence, the induction of vascular AM can be a new target of therapeutic approach to diabetic complications. Copyright

Diabetes and bone metabolism

In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR γ2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARγ agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic β-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures.

Development of silent gastric carcinoid in a type 1 diabetic patient with primer hypothyreosis

Type 1 diabetes is usually associated with other autoimmune diseases. Parietal cell antibodies (PCA) are found in 20% of type 1 diabetic patients which might be an early sign of autoimmune gastritis and pernicious anemia. PCA destroy the gastric H+/K+ ATP-ase. The chronic auto-destruction of the proton pump leads to hypo/achlorhydria and hypergastrinemia which leads to the hyper/dysplasia of enterochromaffin-like cells (ECL). ECL hyper/dysplasia is known to increase the likelihood of gastric carcinoid tumor development in affected patients. Gastric carcinoid tumors forming from the hyperplasia of ECL cells are found in 4-9% of patients having autoimmune gastritis or pernicious anemia. The 29-years-old type 1 diabetic patient, having primer hyperthyroidism was admitted to our clinic because of gastric pain. Results of endoscopy and biopsy showed multiple small polyps in the fundus with non-antral hypergastrinemic (type A) atrophic gastritis. The parietal cell antibody test was positive, the serum chromogranin A level was 289,7 ng/ml (normal value

Plasma ghrelin response to an oral glucose load in growth hormone-deficient adults treated with growth hormone

98 ng/ml), TSH level was 9,93 mIU/L. The histological examination indicated carcinoid tumor. Sandostatin therapy was started then partial gastrectomy was done. After the operation the plasma chromogranin level normalized. Non-antral, multiple polyps could cover silent neuroendocrine tumors, which are slowly growing benign endocrine tumors, however, they also might be high malignity endocrine carcinomas. These tumors could be easily recognized in the clinical practice by measuring the serum or tissue chromogranin A level and other markers of tumor growth. Thus screening of gastric endocrine tumors in type 1 diabetic patients with co-morbid autoimmune diseases is recommended.

Tünetmentes gyomorcarcinoid kialakulása 1-es típusú diabéteszben és primer hypothyreosisban szenvedo betegben

ZusammenfassungHINTERGRUND: Die Pathophysiologie der Ghrelin-Sekretion bei Wachstumshormon-defizienten Erwachsenen unter Therapie mit Wachstumshormon ist weitgehend unbekannt. Auch die Beziehung zwischen Plasma-Ghrelin-Spiegeln und einer durch eine orale Glukosebelastung induzierten Hyperinsulinämie wurde in solchen Patienten noch nicht erforscht. ZIEL DER STUDIE: In der vorliegenden Studie untersuchten wir die Beziehung zwischen Plasma-Ghrelin, Insulin, C-Peptid und Leptin nach einer oralen Glukosebelastung bei Wachstumshormon-defizienten Erwachsenen, die unter einer Therapie mit Wachstumshormon standen. METHODEN: Plasma-Ghrelin, Leptin, Insulin, C-Peptid und Blutzucker wurden vor sowie 30, 60, 90 und 120 Minuten nach der oralen Einnahme von 75 g Glukose bei 20 Wachstumshormon-defizienten Erwachsenen (12 Frauen, 8 Männer), die 7,2 ± 1,3 (MW ± SE) Jahre mit Wachstumshormon behandelt worden waren, gemessen. Plasma-Ghrelin wurde vor und nach einer Glukosebelastung bei 10 gesunden im Alter und Gewicht entsprechenden Personen (5 Männer, 5 Frauen) gemessen. ERGEBNISSE: Die orale Glukosebelastung bewirkte bei Wachstumshormon-defizienten Patienten und bei Gesunden eine prozentuell ähnliche Unterdrückung des Plasma-Ghrelins. In beiden Gruppen sank das Plasma-Ghrelin 30 Minuten nach der Glukosegabe signifikant und blieb von da ab bis zum Ende der Untersuchung unterdrückt. Bei den Wachstumshormon-defizienten Patienten zeigten Insulin (basal 15,9 ± 3,9 µIU/ml) und C-Peptid (basal (2,5 ± 0,3 ng/ml) gegenläufige Veränderungen mit Spitzenwerten 30 Minuten (Insulin: 109,5 ± 15,6 µIU/ml) bzw. 60 Minuten (C-Peptid: 10,3 ± 1,1 ng/ml) nach der Glukosegabe. Zum Unterschied vom basalen Ghrelin korrelierte bei diesen Patienten das post-Glukose Plasma-Ghrelin negativ mit dem Plasma-Insulin, dem C-Peptid und den Blutzuckerwerten. Das basale Ghrelin korrelierte invers mit dem basalen Plasma-Leptin. SCHLUSSFOLGERUNGEN: Die Unterdrückung von Plasma-Ghrelin nach einer oralen Glukosebelastung bei Wachstumshormon-defizienten Patienten unter Wachstumshormon-Therapie ist ähnlich der bei Gesunden beobachteten; dies spricht gegen eine gestörte Regulation der Ghrelin-Sekretion bei diesen Patienten. Die Korrelationen zwischen post-Glukose Plasma-Ghrelin, Insulin und Blutzucker machen einen schon früher vorgeschlagenen Zusammenhang zwischen einer Hyperinsulinämie (bzw. einem erhöhten Blutzucker) und der Suppression der Ghrelin Spiegel wahrscheinlich.SummaryBACKGROUND: Little is known about the pathophysiology of ghrelin secretion in growth hormone-deficient adults treated with growth hormone, and the relationship between plasma ghrelin and hyperinsulinemia induced by an oral glucose load has not been investigated in these patients. OBJECTIVE: In the present study we examined the relationship between plasma ghrelin, insulin, C-peptide and leptin after an oral glucose load in growth hormone-deficient adults receiving treatment with growth hormone. METHODS: Plasma ghrelin, leptin, insulin, C-peptide and blood glucose were measured before and then at 30, 60, 90 and 120 min after the ingestion of glucose (75 g orally) in 20 growth hormone-deficient adults (12 women and 8 men), who had been treated with growth hormone for 7.2 ± 1.3 years (mean ± SE). Plasma ghrelin was also determined before and after the glucose load in 10 age-and weight-matched healthy persons (5 women and 5 men). RESULTS: The oral glucose load induced a similar percent suppression of plasma ghrelin in the growth hormone-deficient patients and in the healthy persons. In both groups plasma ghrelin decreased significantly 30 min after the glucose load and remained suppressed throughout the test period. In the patients plasma insulin (baseline, 15.9 ± 3.9 µIU/ml) and C-peptide (baseline, 2.5 ± 0.3 ng/ml) showed opposite changes with peak responses at 30 min (insulin, 109.5 ± 15.6 µIU/ml) or 60 min (C-peptide, 10.3 ± 1.1 ng/ml). In these patients, post-glucose, but not baseline plasma ghrelin levels correlated negatively with plasma insulin, C-peptide and blood glucose levels, whereas baseline plasma ghrelin correlated inversely with baseline plasma leptin. CONCLUSIONS: The similar suppression of plasma ghrelin in growth hormone-deficient patients treated with growth hormone and in healthy persons after an oral glucose load argues against disturbed regulation of ghrelin secretion in these patients. The correlations between post-glucose plasma ghrelin, insulin and blood glucose support the existence of a previously proposed link between hyperinsulinemia (or increased blood glucose) and suppression of ghrelin levels.

Tünetmentes gyomorcarcinoid kialakulása 1-es típusú diabéteszben és primer hypothyreosisban szenvedő betegben@@@Development of silent gastric carcinoid in a type 1 diabetic patient with primer hypothyreosis

Type 1 diabetes is usually associated with other autoimmune diseases. Parietal cell antibodies (PCA) are found in 20% of type 1 diabetic patients which might be an early sign of autoimmune gastritis and pernicious anemia. PCA destroy the gastric H+/K+ ATP-ase. The chronic auto-destruction of the proton pump leads to hypo/achlorhydria and hypergastrinemia which leads to the hyper/dysplasia of enterochromaffin-like cells (ECL). ECL hyper/dysplasia is known to increase the likelihood of gastric carcinoid tumor development in affected patients. Gastric carcinoid tumors forming from the hyperplasia of ECL cells are found in 4-9% of patients having autoimmune gastritis or pernicious anemia. The 29-years-old type 1 diabetic patient, having primer hyperthyroidism was admitted to our clinic because of gastric pain. Results of endoscopy and biopsy showed multiple small polyps in the fundus with non-antral hypergastrinemic (type A) atrophic gastritis. The parietal cell antibody test was positive, the serum chromogranin A level was 289,7 ng/ml (normal value

Insulin treatment decreases the antioxidant defense mechanism in experimental diabetes.

98 ng/ml), TSH level was 9,93 mIU/L. The histological examination indicated carcinoid tumor. Sandostatin therapy was started then partial gastrectomy was done. After the operation the plasma chromogranin level normalized. Non-antral, multiple polyps could cover silent neuroendocrine tumors, which are slowly growing benign endocrine tumors, however, they also might be high malignity endocrine carcinomas. These tumors could be easily recognized in the clinical practice by measuring the serum or tissue chromogranin A level and other markers of tumor growth. Thus screening of gastric endocrine tumors in type 1 diabetic patients with co-morbid autoimmune diseases is recommended.