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Adipokines are a family of hormones and cytokines with both pro- and anti-inflammatory effects released into the circulation to exert their hormonal effects. Adipokines are closely involved in most metabolic pathways and play an important modulatory role in lipid and carbohydrate homeostasis as they are involved in the pathophysiology of most metabolic disorders. Incretin-based therapy is a newly introduced class of antidiabetic drugs that restores euglycemia through several cellular processes; however, its effect on adipokines expression/secretion is not fully understood. In this review, we propose that incretin-based therapy may function through adipokine modulation that may result in pharmacologic properties beyond their direct antidiabetic effects, resulting in better management of diabetes and diabetes-related complications.

Purpose: Non-alcoholic fatty liver (NAFL) is comorbid to obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). It is unclear whether NAFLD constitutes a direct risk factor for macrovascular disease in T2DM. This study aimed at revisiting the cardiometabolic traits linked to NADL and micro-/ macrovascular complications in a biethnic Caucasian and African cohort. Methods: Cross-sectional analysis of 568 of T2DM patients (515 Caucasians; 53 Africans) in whom the presence of NAFL was identified by ultrasonography and the cardiometabolic phenotype was exhaustively characterized, including carbohydrate homeostasis, comprehensive lipidogram including Lp(a), cumulative exposure to hyperglycemia, and prevalent micro/macrovascular complications. Results: FL was present in 73% of Caucasians and 36% of Africans (p − in both groups. A marked reduction in diabetic retinopathy (DR), ocular hypertonia and cataracts were found in FL+ of the two ethnicities. In FL+ Caucasians, relative risk of DR was −38%, cataracts −35%, and ocular hypertonia −42%. In FL+ Africans, risk of overall microangiopathy was −66% and that of DR −86%. Conclusions: An inverse association was observed between NAFL and the presence of diabetic retinopathy, cataract and ocular hypertonia. The ophthalmoprotection conferred by liver steatosis was found in Caucasians and Africans. Among the latter, hepatic steatosis was linked to lower lipoprotein(a) levels. There was no association between hepatic steatosis and prevalent macrovascular complications in neither of the two ethnic groups.

In recent years, the possibility of using intranasally administered insulin to treat Alzheimers disease and other cognitive disorders has been widely studied. At the same time, the possibility of its use in the treatment of diabetes mellitus is practically not investigated, which is due to the insufficient study of the molecular mechanisms of its action on the hormonal and metabolic status of the organism. The review discusses literature data and the results of our own research on the role of insulin in the central regulation of energy homeostasis, as well as on the experience of using intranasally administered insulin to correct eating disorders and metabolic and hormonal dysfunctions developing under conditions of experimental diabetes mellitus and metabolic syndrome. In studies involving healthy volunteers, various effects of intranasally administered insulin were shown, including effects on cognitive function, eating behavior and weight loss, and the gender specificity of its action was found. In the course of numerous studies of intranasally administered insulin in animal models of diabetes mellitus, not only stabilization of carbohydrate homeostasis was shown, but also a positive effect in the form of restoration of the functional activity of insulin signaling pathways in the hypothalamus and other parts of the brain. We have presented and analyzed data on the systemic effects of intranasally administered insulin in rodents with experimental models of diabetes mellitus, as well as in healthy individuals.В последние годы широко изучается возможность применения интраназально вводимого инсулина для лечения болезни Альцгеймера и других когнитивных расстройств. В то же время практически не исследуется возможность его применения в рамках терапии сахарного диабета, что во многом связано с недостаточной изученностью молекулярных механизмов его действия на гормональный и метаболический статусы организма. В обзоре обсуждаются данные литературы и результаты собственных исследований о роли инсулина в центральной регуляции энергетического гомеостаза, а также об опыте применения интраназально вводимого инсулина для коррекции нарушений пищевого поведения и метаболических и гормональных дисфункций, развивающихся в условиях экспериментального сахарного диабета и метаболического синдрома. В исследованиях с участием здоровых добровольцев были показаны различные эффекты интраназально вводимого инсулина, в том числе влияние на когнитивные функции, пищевое поведение и снижение массы тела, а также обнаружена гендерная специфичность его действия. В ходе многочисленных исследований интраназально вводимого инсулина на животных моделях сахарного диабета были показаны не только стабилизация углеводного гомеостаза, но и положительное действие в виде восстановления функциональной активности инсулиновых сигнальных путей в гипоталамусе и других отделах мозга. Нами представлены и проанализированы данные о системных эффектах интраназально вводимого инсулина у грызунов с экспериментальными моделями сахарного диабета, а также у здоровых индивидуумов.

The increasing burden of obesity worldwide and its effect on cardiovascular disease (CVD) risk is an opportunity for evaluation of preventive approaches. Both obesity and CVD have a genetic background and polymorphisms within genes which enhance expression of variant proteins that influence CVD in obesity. Genome-based prediction may therefore be a feasible strategy, but the identification of genetically driven risk factors for CVD manifesting as clinically recognized phenotypes is a major challenge. Clusters of such risk factors include hyperglycaemia, hypertension, ectopic liver fat, and inflammation. All involve multiple genetic pathways having complex interactions with variable environmental influences. The factors that make significant contributions to CVD risk include altered carbohydrate homeostasis, ectopic deposition of fat in muscle and liver, and inflammation, with contributions from the gut microbiome. A futuristic model depends on harnessing the predictive power of plausible genetic variants, phenotype reversibility, and effective therapeutic choices based on genotype-phenotype interactions. Inverting disease phenotypes into ideal cardiovascular health metrics could improve genetic and epigenetic assessment, and form the basis of a future model for risk detection and early intervention.

Diabetes mellitus is a chronic, life-threatening metabolic disorder that occurs worldwide. Despite an increase in the knowledge of the risk factors that are associated with diabetes mellitus, its worldwide prevalence has continued to rise; thus, necessitating more research into its aetiology. Recent researches are beginning to link a dysregulation of the circadian rhythm to impairment of intermediary metabolism; with evidences that circadian rhythm dysfunction might play an important role in the aetiology, course or prognosis of some cases of diabetes mellitus. These evidences thereby suggest possible relationships between the circadian rhythm regulator melatonin, and diabetes mellitus. In this review, we discuss the roles of the circadian rhythm in the regulation of the metabolism of carbohydrates and other macronutrients; with emphasis on the importance of melatonin and the impacts of its deficiency on carbohydrate homeostasis. Also, the possibility of using melatonin and its analogs for the “prophylaxis” or management of diabetes mellitus is also considered.

Nowadays, an acute myocardial infarction is one of the leading causes of mortality among the population. The EHS-DH registry data clearly illustrate the association between the comorbidities and high mortality following acute myocardial infarction during a year period of follow up. The pronounced influence of carbohydrate metabolism disturbances on the survival of such patients has already been reported. The aim of the study was to analyze the immune inflammation relationships based on assessing calprotectin and the parameters of lipid and carbohydrate metabolism, to evaluate the presence and nature of the relationship between these parameters and carbohydrate metabolism parameters based on the study of blood glucose, insulin and insulin resistance (by the indices HOMA, QUICKI, Caro), anthropometric indicators and inflammatory indicators (monocyte and neutrophile levels). Materials and methods. The study included 64 patients (mean age 65, 31 ± 1.62 years) with acute myocardial infarction and concomitant diabetes mellitus type 2. The design of the study included the primary laboratory investigation of patients during the first day since the onset of acute myocardial infarction with the elevation of the ST segment before the initiation of thrombolytic therapy or percutaneous intervention. The direct correlation between the calprotectin concentration and the HOMA insulin resistance index (R = 0.52; p 0.05 and R = 0.18; p> 0.05, respectively). Conclusions. The increase in the body mass index and the activity of serum monocytes and neutrophils is associated with high concentrations of calprotectin that is accompanied by disturbances of carbohydrate homeostasis towards the growth of insulin resistance and changes of lipidograms of proatherrogenic nature.

Bile acid receptors regulate lipid homeostasis, carbohydrate homeostasis, drug metabolism, energy consumption and inflammatory responses in response to bile acids and drugs. Cardiovascular diseases such as atherosclerosis and vascular calcification are major complications in patients with diabetes mellitus, chronic kidney disease, dyslipidemia and aging. Cardiovascular complications have a risk of mortality and morbidity worldwide. Bile acid modulators including agonists and antagonists are effective at treating cardiovascular diseases and improving outcomes. In this chapter, we summarize basic bile acid receptor signaling and functions, and effects of bile acid receptor modulations in the development of cardiovascular diseases.

Apolipoprotein CIII (ApoCIII), a small protein that resides on the surface of lipoprotein particles, is a key regulator of triglyceride metabolism. The inhibition of lipoprotein lipase (LPL), the increased assembly and secretion of very low-density lipoproteins (VLDL) and the decreased reuptake of triglyceride-rich lipoproteins (TRLs) by the liver are mechanisms associating elevated serum ApoCIII levels and hypertriglyceridemia. ApoCIII concentration is high in individuals with diabetes mellitus, indicating a possible positive correlation with impairment of glucose metabolism. The aim of this review (based on a Pubmed search until August 2018) is to present the possible mechanisms linking ApoCIII and deterioration of carbohydrate homeostasis. ApoCIII enhances pancreatic β-cells apoptosis via an increase of the cytoplasmic Ca2+ levels in the insulin-producing cells. In addition, overexpression of ApoCIII enhances non-alcoholic fatty liver disease and exacerbates inflammatory pathways in skeletal muscles, affecting insulin signalling and thereby inducing insulin resistance. Moreover, recent studies reveal a possible mechanism of body weight increase and glucose production through a potential ApoCIII-induced LPL inhibition in the hypothalamus. Also, the presence of ApoCIII on the surface of high-density lipoprotein particles is associated with impairment of their antiglycemic and atheroprotective properties. Modulating ApoCIII may be a potent therapeutic approach to manage hypertriglyceridemia and improve carbohydrate metabolism.

Clinical trials and meta-analyses have shown that statins can dose dependently increase the incidence of new-onset diabetes mellitus (DM) especially in patients with underlying abnormalities of carbohydrate homeostasis. Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low-density lipoprotein (LDL) receptor expression. Additionally, Mendelian randomization studies have shown that genetic variants as proxies of other drugs that increase LDL receptor expression (ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) also increase the risk of new-onset DM. This concept is supported by the fact of decreased DM prevalence in patients with familial hypercholesterolemia who have decreased LDL receptor expression. In contrast, hypolipidemic drugs, such as the cholesteryl ester transfer protein inhibitors, that decrease LDL cholesterol without directly interfering with the LDL receptor expression do not seem to detrimentally affect carbohydrate homeostasis. However, the clinical trials of ezetimibe and PCSK9 inhibitors have not shown an increased DM risk, possibly suggesting that other potential non-well-defined "off-target effects" of hypolipidemic drugs may affect carbohydrate homeostasis. Thus, the long-term effect of hypolipidemic drugs on DM risk depends not only on their final mechanism of hypolipidemic action but also on other "on-target" and "off-target" effects of these drugs.

Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-β HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established.

Hypoglycemia in the neonatal period is one of the urgent problems of pediatric endocrinology. The main factors that lead to disruption of carbohydrate homeostasis are generally known, but the issues of neonatal hypoglycemia continue to be actively studied. In the last few years, the effect of low blood glucose on brain neurons has been studied, the issues of glycemia monitoring in the first days of life have been outlined, and strategies for managing newborns with hypoglycemic syndrome are being discussed.Гипогликемии в периоде новорожденности являются одной из актуальных проблем детской эндокринологии. Основные факторы, приводящие к нарушению гомеостаза углеводов, в целом известны, однако вопросы неонатальных гипогликемий продолжают активно изучаться. В последние годы исследуется влияние низкого уровня глюкозы крови на нейроны головного мозга, дискутируются вопросы мониторинга гликемии в первые дни жизни, обсуждается тактика ведения новорожденных с гипогликемическим синдромом.

Statins are the cornerstone of lipid-lowering treatment in patients with or without type 2 diabetes. Prospective randomized clinical trials and meta-analyses have shown that the statin-mediated decrease in plasma low-density lipoprotein cholesterol (LDL-C) is associated with a significant decrease in cardiovascular (CV) morbidity and mortality. Furthermore, high-intensity statin treatment in high-risk individuals is followed by a significantly greater decrease in CV events compared with moderate dose statin treatment. However, the majority of high-risk individuals do not attain the LDL-C targets set by the guidelines even if high-intensity statin therapy is used. This is especially relevant in diabetic patients who need aggressive lipid management to decrease macrovascular complications. To further decrease this residual CV risk associated with suboptimal reduction in LDL-C levels, combination lipid-lowering treatment (eg, statin þ ezetimibe) is an attractive option. Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) protein and thus decreases cholesterol absorption from the gastrointestinal tract leading to a further fall in plasma LDL-C concentration by 20% to 25% when added to ongoing statin therapy. The recently published results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study showed, for the first time, that the additional ezetimibe-induced decrease in LDL-C levels (compared with simvastatin monotherapy) is associated with a significant further decrease in major CV events in very high-risk patients with acute coronary syndrome. Thus, the IMPROVE-IT trial confirms the LDL-C story. A lower LDL-C concentration is better for the reduction in CV events. These findings also refute any hypothesis that focuses on LDL-C–independent pleiotropic effects of statins. Additionally, a recently published meta-analysis of randomized controlled trials showed that adding ezetimibe to statin therapy not only decreases LDL-C concentration but also reduces CV events (relative risk: 0.92, P 1⁄4 .004). The IMPROVE-IT trial showed that elderly individuals and diabetic patients gain greater benefit from the addition of ezetimibe (Table 1). Interestingly, the addition of ezetimibe to ongoing statin therapy may induce a greater reduction in plasma LDL-C levels in diabetic patients compared with nondiabetic individuals. It is worth mentioning that the incidence of side effects (including cancer) in the IMPROVE-IT trial was not different between the statin and the statin þ ezetimibe combination groups. This finding not only confirms the long-term safety of ezetimibe but also that of very low LDL-C levels. Furthermore, recently published Mendelian randomization studies have also confirmed the benefits of decreased cholesterol absorption, which is associated with reduction in LDL-C concentration, in terms of CV disease. These studies showed that genetic polymorphisms of the NPC1L1 gene, which can be used as a proxy of ezetimibe therapy that targets the NPC1L1 protein, are not only associated with a reduction in LDL-C levels but also with a reduction in CV events (Table 2). Thus, combination therapy of statins with ezetimibe is a reasonable, effective, and safe option to treat diabetic dyslipidemia. Nowadays, fixed-dose combinations of a statin with ezetimibe are currently, or awaiting to be, marketed. The fixed-dose atorvastatin þ ezetimibe combination is especially attractive, since it can substantially increase adherence to statin therapy, while atorvastatin (the most commonly used statin in many countries) has the unique properties of lower renal excretion and fewer interactions with other commonly used drugs compared with simvastatin. Further analysis of the results of the IMPROVE-IT trial will clarify the role of ezetimibe (and of statin þ ezetimibe combination therapy) in carbohydrate homeostasis. Some recently published preliminary data hint that ezetimibe might favorably affect insulin resistance and carbohydrate metabolism, in part due to its ability to stimulate intestinal glucagon-like peptide 1 secretion via the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. It is worth mentioning that ezetimibe can also exhibit pleiotropic effects

The oyster insulin-related peptide (oIRP) is known in other organisms to play important roles in growth control and carbohydrate homeostasis. Polymorphisms of the oIRP gene were evaluated for associations with growth performance of 271 Crassostrea gigas individuals from a diallel cross among three strains of C. gigas. Thirty-one single nucleotide polymorphisms (SNPs) were revealed in 1.5 kb of the oIRP gene, and six of them were significantly associated with growth performance (P < 0.05), particularly for T1358G and G1437A which were highly correlated with all the five growth traits (shell height, shell length, shell width, body mass and soft-tissue mass) (P < 0.01). Moreover, haplotypes analysis revealed that H7 (ATGTGA) and H8 (ATGTTA) might be the most advantageous haplotypes for growth traits. The results demonstrated that the oIRP gene could influence growth performance of C. gigas and have potential applications in future genetic improvement of C. gigas.

Diabetes mellitus (DM) is a serious and growing worldwide health problem and is associated with se- vere acute and chronic complications that negatively influence both quality of life and survival of affected individuals. It is a heterogeneous deregulation of car- bohydrate metabolism. The liver is a central regulator of carbohydrate homeostasis and releases glucose according to metabolic demands. In the last years, the liver injury has been recognized as a major complica- tion of DM. In fact, evidence suggests that in diabetic patients, the mortality rate due to liver cirrhosis is even higher than that due to cardiovascular disease and it has been suggested that there is a two-fold in- creased risk of liver disease in diabetic patients. Among the different types of diabetes, we analyze type 1 dia- betes mellitus as a chronic disorder and an inflam- matory process, which is also associated with in- creased risk of chronic liver injury. Animal models have contributed extensively to the study of diabetes, and it is well established that administration of a unique dose of streptozotocin (STZ) induces insulin- dependent type 1 diabetes mellitus. We analyzed the contribution of Tumor Necrosis Factor alpha (TNF-α) intracellular pathway and oxidative stress in the de- velopment of apoptosis in the liver of streptozotocin- induced diabetic animals. In this review, we describe the role of upstream mediators of the interaction be- tween TNF-α and its receptor, TNF-R1, by assessing the ability of the in vivo treatment with etanercept (TNF-α blocking antibody) to protect against TNF-α- induced apoptosis. Also, we studied the role of iNOS- induction in the TNF-α-induced liver apoptosis by type 1 diabetes, by treatment of diabetic rats with aminoguanidine (selective iNOS inhibitor), which blocked the induction of apoptosis. Interestingly, iNOS inhibition significantly reduced TNF-α levels, evidencing an interaction between TNF-α and iNOS activity. On the other hand, we found that the ad- ministration of antioxidants/hydroxyl radical scaven- gers (Tempol and Desferal) prevented oxidative stress by reducing the effects of hydroxyl radical production and both lipid peroxidation (LPO) levels and apop- tosis. Taken together, our studies support that, at least in part, the hydroxyl radical acts as a reactive inter- mediate, which leads to liver apoptosis in a model of STZ-mediated hyperglycemia. Conclusion and Future: The relevance of the present review is to provide fur- ther knowledge about the mechanisms which may contribute to the disease process in the liver during the course of an inflammatory process as it is type 1 diabetes. Regulation of hepatic TNF-α levels and oxi- dative stress in the diabetic state could be of thera- peutic relevance for the improvement or delay of the hepatic complications linked to chronic hyperglycemia. Fil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina Fil: Ingaramo, Paola Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina Fil: Ronco, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina Fil: Carnovale, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina

Background Most recently, a novel myokine, named irisin, was identified in human that expressed by skeletal muscle after exercise. Irisin increases energy expenditure by turning white adipose tissue into brown adipose tissue. Thus improves carbohydrate homeostasis in humans. Irisin is considered as a potential biomarker for obesity and metabolic syndrome. In recent years, numerous studies have been conducted about irisin with adults, although number of studies with newborns is limited. Objective To evaluate cord blood irisin level with small gestational age (SGA) and appropriate gestational age (AGA) in term newborns. Methods A cross-sectional study of 34 AGA and 34 SGA term newborns who were born in (1–30) December 2015 in Fatih University Hospital. Estimated fetal weight were calculated using the Hadlock formula by gynecologists to pregnant women in second trimester. All the babies were classified at birth as SGA or AGA. SGA was defined according to the Lubchenco scale for gender and gestational age. We collected umbilical cord blood at the time of delivery. Cord blood irisin levels were measured using commercial enzyme-linked immunosorbent assays in our hospital laboratory. Results Cord blood irisin levels were significantly lower in SGA group [median 30 (25 ± 8) ng/ml] than in AGA group [median 40 (39 ± 13) ng/ml, p 0.05). Mothers with gestational diabetes, hypertension, asthma, chronic disease, use of drug or a history of smoking exposure were excluded from the study. When the study data were evaluated, Yates Continuity Correction and Fisher’s exact tests were used in descriptive statistical methods and for comparison of qualitative data. Conclusion Our results support the idea that irisin have a physiologic role in neonates. Low level of irisin is associated with the impaired carbohydrate metabolism in term infants with SGA. However, further studies with larger series are warranted to confirm this.

Introduction The causal role of sympathetic nervous system in the development of metabolic disorders has not been clearly defined. The aim of the study was to determine if a chronic increase of the sympathetic nervous activity can induce and/or accelerate the development of glucose metabolism disorders. For that purpose, we used a transgenic mouse model, in which the gene encoding for the reuptake norepinephrine transporter (NET) has been deleted; these animals display increased urinary catecholamine levels. Methods Carbohydrate homeostasis (intraperitoneal glucose tolerance test, IPGTT, insulin tolerance test, ITT, insulin rates) was studied in heterozygous NET knockout mice (±) or wild-type mice (+/+) at 10, 20 and 25 weeks old. Mice were then fed either with normal chow or 30% w/v fructose in drinking water; glucose metabolism was assessed again after 15 weeks of such diet. Results Heterozygous mice displayed glucose intolerance already at 10 weeks old (area under the curve of the IPGTT (AUC; %) = 24859 vs 18016, p=0.004); similar results were obtained at 25 weeks old, i.e, just before starting the fructose diet: AUC = 24524 vs 20573, p=0.005 for ± and +/+ mice respectively. Moreover sensibility to insulin seemed to be diminished in ± mice compared to +/+ mice (insulin rate = 1.12 vs 0.86 μg/L and HOMAIR= 11.1 vs 8.4). Heterozygous animals were also much more sensitive to high fructose, since a 20% increase in the AUC of the IPGTT was obtained at the end of the high fructose diet, compared to the 2% increase in +/+ mice. This was associated with a decrease of insulin sensibility (HOMA-IR of ± mice = 11.1 vs 18.1, p=0.01, before and after fructose diet respectively). Conclusion Our data show that constitutive chronic sympathetic hyperactivity can induce the early development of carbohydrate metabolism disorders. Moreover, it seems to represent a major factor of susceptibility to diet-induced metabolic dysfunction. The author hereby declares no conflict of interest

Nonalcoholic fatty liver disease (NAFLD) spans a pathological spectrum from nonalcoholic steatosis to steatohepatitis. The pathophysiology of this disorder is complex, but includes insulin resistance and disrupted lipid and carbohydrate homeostasis, which at a subcellular level results in oxidative stress, free fatty acid-mediated lipotoxicity, defects in mitochondrial function, endoplasmic reticulum stress and cytokine-mediated toxicity. In chronic hepatitis C (CHC), systemic metabolic derangements similar to NAFLD may be operative, but in addition, virus-specific factors contribute to steatosis. The mechanisms for steatosis in CHC appear to share common pathways with those observed in NAFLD. This article outlines our current understanding of the subcellular mechanisms of steatosis in NAFLD and CHC, including their similarities and differences.

We have studied the impact of liquid diets formulated for complete or supplemental enteral nutrition of type II, non insulin-dependent (NIDDM) diabetics on carbohydrate homeostasis. To achieve this, liquid formula tolerance tests were performed in NIDDM patients under an oral treatment regimen with a combination of diet plus glibenclamide (7 men, 3 women, age: 56 +/- 11 years; mean body mass index of 26.2 +/- 3.6 kg/m2). After an overnight fast, each patient received the usual morning medication and, thereafter, ingested formula diet in randomized order with 10 day intervals between tests. 500 ml were administered of either a standard liquid diet (Biosorb Sonde), a fibre containing diet (Biosorb Plus Sonde), or a carbohydrate modified, fructose containing "diabetes" diet (Fresubin Diabetes) (carbohydrate contents of approximately equal to 60 g, respectively). Blood samples were collected over 180 min. Considering minor variations in the nutritional values of the diets, IR-insulin, IR-C-peptide, IR-glucose-dependent insulinotropic polypeptide (GIP), and IR-glucagon-like peptide. 1 (GLP-1) in plasma did not significantly differ between the study groups. After ingestion of Biosorb Sonde area under the curve glucose was greater than that seen after uptake of fibre containing or carbohydrate modified, i.e. fructose containing "liquid diabetes diets". All diets challenged the entero-insular axis in non-insulin dependent diabetics to a comparable extent. This data does not support the contention to employ special "diabetes" formulas for enteral nutrition of patients with NIDDM.

ATIENTS undergoing major surgery encounter stereotypical alterations in carbohydrate and protein metabolism often referred to as the catabolic response. Characteristic features of impaired carbohydrate homeostasis are increased production of glucose combined with decreased glucose utilization resulting in hyperglycemia. The magnitude of hyperglycemia depends on the severity of surgical tissue trauma. In fasting non-diabetic patients undergoing elective intra-abdominal operations, blood glucose levels increase to 7–10 mmol·L –1 . During cardiac surgery, blood glucose values frequently exceed 15 mmol·L –1 in non-diabetic patients and 20 mmol·L –1 in diabetic subjects. Protein catabolism is characterized by a net loss of body protein. In metabolically healthy patients cumulative nitrogen losses, after elective abdominal operations, range between 40 and 80 g, equivalent to 1.2 to 2.4 kg lean tissue. Postoperative protein loss in patients with type 2 diabetes is 50% greater than in their non-diabetic counterparts. 1 Much of the catabolic profile can be explained by specific neuroendocrine changes, including increased circulating concentrations of cortisol, glucagon, and catecholamines. These hormones exert catabolic effects, either directly or indirectly, by inhibiting insulin secretion and/or counteracting its peripheral action leading to the impairment of tissue insulin sensitivity. The extent of insulin resistance depends on the intensity of trauma, suggesting that insulin resistance is a marker of surgical stress. Clinical significance of the catabolic response to surgery Evidence is mounting that even moderate increases in blood glucose are associated with adverse outcomes. Patients with fasting glucose levels > 7 mmol·L –1 or random blood glucose levels > 11.1 mmol·L –1 on general surgical wards showed an 18-fold increase in in-hospital mortality, a longer length of stay, and a greater risk of infection. 2 In critically ill patients, mortality was directly correlated with increasing glucose levels above 5 mmol·L –1 . 3 In patients undergoing cardiovascular procedures, hyperglycemia was associated with increased mortality and organ dysfunction. 4 Furthermore, detrimental effects of acute hyperglycemia were documented in patients with cerebrovascular disease, myocardial ischemia, and trauma. Erosion of lean tissue protein delays wound healing, compromises immune function, and diminishes muscle strength after surgery. The resulting muscle weakness prolongs mechanical ventilation, inhibits effective coughing, and impedes mobilization. The length of time for return of normal physiologic function after discharge from the hospital is related to the extent of loss of lean body mass during hospitalization. 5

The prevalence of the metabolic syndrome is increasing owing to lifestyle changes leading to obesity. This syndrome is a complex association of several interrelated abnormalities that increase the risk for cardiovascular disease and progression to diabetes mellitus (DM). Insulin resistance is the key factor for the clustering of risk factors characterizing the metabolic syndrome. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III defined the criteria for the diagnosis of the metabolic syndrome and established the basic principles for its management. According to these guidelines, treatment involves the improvement of the underlying insulin resistance through lifestyle modification (eg, weight reduction and increased physical activity) and possibly by drugs. The coexistent risk factors (mainly dyslipidemia and hypertension) should also be addressed. Since the main goal of lipid-lowering treatment is to achieve the NCEP low-density lipoprotein cholesterol (LDL-C) target, statins are a good option. However, fibrates (as monotherapy or in combination with statins) are useful for the treatment of the metabolic syndrome that is commonly associated with hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) levels. The blood pressure target is

Infants born small for gestational age (SGA) are at risk to develop metabolic complications. Insulin-like growth factor 1 (IGF-1) resistance due to IGF-1 receptor (IGF1R) mutations is a rare genetic condition that causes proportionate growth retardation. The contribution of an impaired IGF1R function to the development of comorbidities such as disturbed glucose homeostasis is not well understood. Genetic analysis and detailed auxological, endocrine and psychological investigations in two male SGA siblings were performed. The two patients and their father bear a novel heterozygous mutation (p.Cys1248Tyr) in the IGF1R gene. Both brothers displayed very similar growth pattern before and during recombinant human growth hormone treatment, whereas oral glucose tolerance tests showed variable manifestations of progressive impaired glucose tolerance. The father had already developed type 2 diabetes mellitus. Growth retardation in our patients is likely caused by the IGF1R mutation that might predispose to disturbances of carbohydrate homeostasis. Therefore, a close metabolic monitoring of affected patients is indicated, particularly if growth hormone therapy is commenced.

The Enteroendocrine cells form the largest endocrine system in the body. They secrete multiple regulatory molecules which control physiological and homeostatic functions particularly postprandial regulation of glucose and GIT motility (Sternini et al. 2008).In Diabetic setting, it is speculated that enteroendocrine cells which secrete hormones involved in carbohydrate metabolism will undergo changes aimed at maintaining carbohydrate homeostasis (Stephanie et al. 2009).To determine how enteroendocrine cells respond to diabetes and their likely role in diabetic complications, Sixty albino Wister rats (male=30 and female =30), weighing between 200-300g were divided into five experimental groups (n=10) per group and a control (n=10) . Diabetes mellitus was induced with a single intraperitoneal dose of 65mg per kg of streptozotocin. Blood was sample from tail vein 30 minutes after the application of EMLAR cream (2.5% lignocaine and 2.5% prilocaine) for glucose test and only those with blood glucose within the ...

It seems that in both diabetic and non-diabetic postmenopausal women unopposed oestradiol replacement therapy is followed by an improvement in glucose homeostasis and a slight improvement or a neutral effect on insulin sensitivity. When progestogens are added, the beneficial oestrogen-induced effect on glucose metabolism is impaired or at least neutralised (partly dependent on the choice of progestogen). This also applies to the oestrogen effect on insulin sensitivity. An ideal progestogen should not abolish the positive effects on glucose metabolism by oestrogens and simultaneously decrease triglyceride levels in women with type 2 diabetes.

A predominance of small, dense low-density lipoprotein (LDL) particles (subclass pattern B) has been associated with a 2- to threefold increase in coronary heart disease risk. Recently, it has been reported that LDL subclass pattern B is associated with hyperfibrinogenemia, which is also a coronary heart disease risk factor. The present study examined the relation between hyperfibrinogenemia and LDL subclass pattern in 258 postmenopausal women. A significant univariate correlation was observed between the concentration of cholesterol carried in small, dense LDL particles and plasma fibrinogen concentration (r = 0.17, p = 0.01). The prevalence of LDL subclass pattern B was 41.9% in the highest fibrinogen tertile, compared with 27.9% and 24.4% in the first and second tertiles, respectively (global chi-square 6.8, p = 0.03). The crude odds ratio (OR) for LDL subclass pattern B among women in the highest fibrinogen tertile, compared with the lower tertiles, was 2.03 (95% confidence interval [CI] 1.18 to 3.51, p = 0.01). After adjustment for age and plasma lipids (log e triglycerides, LDL cholesterol, and high-density lipoprotein cholesterol), the OR was 2.14 (95% CI 1.17 to 3.96, p = 0.01). Further adjustment for hematocrit, indicators of carbohydrate homeostasis, body mass index, waist circumference, and several variables related to lifestyle did not attenuate this association (OR 2.56, 95% CI 1.27 to 5.27, p = 0.01). These data suggest that hyperfibrinogenemia and LDL subclass pattern B may be 2 components of a common syndrome and suggest that hyperfibrinogenemia may contribute to the increased coronary heart disease risk associated with LDL subclass pattern B.

A brief review is presented of experimental studies conducted over several years (1970s–1990s) on the incretory potential of salivary glands, specifically on their role in the maintenance of carbohydrate homeostasis; a review is also presented of data on the stimulation of this potential by isoproterenol, a β-adrenergic agonist.

Background Irisin, a novel myokine, increases energy expenditure and glucose tolerance and, thus, improves carbohydrate homeostasis in humans. This hormone has potential therapeutic applications for weight loss and improvement in insulin resistance in subjects with obesity and diabetes mellitus type 2 (T2DM). In this cross-sectional study, we aimed to associate circulating levels of irisin and several anthropometric and metabolic parameters among Arab children. Methods A cohort of 153 Saudi children, 81 boys [age: 12·4 ± 3·2 years; BMI: 19·5 ± 5·9 kg/m2] and 72 girls: [age: 12·9 ± 3·2 years; BMI: 20·6 ± 5·2], were examined. Anthropometry was obtained, and fasted bloods were collected for biochemical analyses. Irisin was assessed by a specific enzyme-linked immunosorbent assay (ELISA). Results Girls had higher circulating irisin levels than boys (P = 0·04). There were several significant correlations between circulating irisin and fasting blood glucose (FBG) (r = −0·35, P < 0·001), sagittal abdominal diameter (SAD) (r = −0·34, P < 0·001) and HDL cholesterol (r = 0·17, P = 0·04) across the entire cohort studied. Notably in girls, but not in boys, HOMA-IR correlated negatively with irisin levels (r = −0·32, P = 0·02), as previously noted in adults. FBG was a significant predictor of circulating irisin (R2 = 0·16) followed by SAD. In multivariate linear regression analysis, after controlling for potential confounders such as gender, age and BMI, irisin levels were independently associated with FBG (β = −0·34, P = 0·01), particularly in girls. Conclusion Serum irisin levels were higher in girls than in boys and correlated negatively with HOMA-IR. They were also independently associated with FBG predominantly in girls, suggesting that this hormone may play a crucial role in glucose metabolism from an early age.

Background The exact mechanism for the dramatic effect of surgical procedures for obesity on type 2 diabetes remains unknown. Methods Five diabetic morbidly obese patients and 5 nondiabetic morbidly obese patients undergoing biliopancreatic diversion were compared retrospectively. A 75-g trans-gastrostomy glucose tolerance test was administered on the fifth day postoperatively and a standard 75-g oral glucose tolerance test was performed on the seventh day postoperatively, with blood sampling for measuring plasma glucose and insulin levels at 0, 30, 60, 90, 120, and 180 minutes. Results All 5 diabetic patients were shown, at the same time, still to have diabetes or an impaired glucose tolerance test when tested through the biliopancreatic limb but patients were normal when tested through the new alimentary channel. No significant difference was seen in the nondiabetic patients. Conclusions Biliopancreatic diversion can completely normalize the glycemic cycle in type 2 diabetes patients in the week after the intervention, even before any significant weight loss has occurred. The surgical procedure itself, designed to exclude most of the stomach, duodenum, and part of the jejunum, directly affects carbohydrate homeostasis.

Objective Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. Methods Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. Results The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. Interpretation This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism. ANN NEUROL 2010;67:31–40

There is a definite relation of diuretic treatment to impaired glucose tolerance and biochemical diabetes, and a probable relation to insulin resistance. The effect of diuretics on glucose tolerance is dose-related. Spironolactone does not impair glucose tolerance even at high dosage, but apparent differences between other diuretics may well be due to comparison at doses which are not equivalent. Diuretic-induced changes in carbohydrate metabolism are not conclusively related to altered potassium homeostasis, and impaired glucose tolerance occurs when relatively low doses of thiazide are combined with potassium-sparing agents. The effect of diuretics on glucose tolerance is largely and possibly wholly reversible. These disturbances of carbohydrate homeostasis have been detected by detailed biochemical testing, and their clinical importance is uncertain. In established diabetes, diuretics have a rapid and substantial adverse effect on metabolic control. In non-diabetic subjects diuretics may rarely cause or trigger a serious hyperosmolar non-ketotic diabetic syndrome. This apart, it is not known whether the metabolic changes cause clinical diabetes or lead to microvascular complications in the long-term. It is now established that biochemical diabetes, glucose intolerance and insulin resistance probably do not increase the risk of coronary heart disease in treated hypertensive patients. Diuretics should be avoided in patients with diabetes, otherwise they remain an excellent choice for first-line antihypertensive therapy.

Introduction: It is well recognized that there is a close relationship between TSH and PRL levels. The aim of this study was to evaluate the impact of insulin sensitivity on the association between TSH and PRL in euthyroid obese subjects. Material and Methods: Retrospective cross-sectional analysis was carried out on 165 euthyroid obese or overweight female patients. Prolactin, TSH, free thyroxine (FT4), free triiodothyronine (FT3), fasting plasma levels of insulin and glucose, postprandial levels of glucose, homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and insulin secretion (HOMA-β cell), body weight, height, body mass index (BMI) and waist circumference were assessed. Statistical tests used were unpaired Student's t-test adjusted by Bonferroni's method and Pearson correlations with Bonferroni corrections. Results: There was no significant difference in prolactin levels between insulin sensitive and resistant subjects. Compared to insulin sensitive subjects, TSH levels were higher in insulin resistant subjects but it was not statistically significant. We observed significant positive correlation between prolactin and TSH in insulin sensitive and normoglycemic subjects (r=0.273, p=0.039 and r=0.253, p=0.023, respectively) but this correlation was lost in insulin resistant subjects and subjects who had fasting glucose levels ≥100 mg/dl (r=0.057, p=0.609 and r=0.090, p=0.404, respectively). Conclusions: The findings of this study provide some clues about the relationship between PRL and TSH in insulin sensitive obese subjects. The insulin sensitivity and carbohydrate homeostasis seem to be involved in relationship with PRL and TSH by the brain via serotoninergic and dopaminergic system. © J. A. Barth Verlag in Georg Thieme Verlag KG.

Pheochromocytoma, a neuroendocrine tumor, is often associated with hyperglycemia. To investigate the underlying pathogenetic mechanisms, five patients (3 women and 2 men, aged 49+/-2.5, mean+/-SD) with benign adrenal pheochromocytoma were studied with an oral glucose tolerance test (OGTT) and the euglycaemic clamp technique. They were studied preoperatively without taking any medication (stage I), after taking an alpha adrenergic receptor blocking agent (stage II), after taking both an alpha and a beta adrenergic receptor blocking agent (stage III), and after surgical removal of the tumor (stage IV). Before any treatment, fasting blood glucose levels and glucose levels during the OGTT were pathologic in all patients. In all patients, mean glucose levels of the OGTTs performed at the three preoperative stages of the study were significantly higher than those of the OGTT performed postoperatively (ANOVA, alpha

MitoNEET is an outer mitochondrial membrane protein that, upon overexpression in white adipose tissue (WAT), exerts a positive impact on tissue expansion and whole-body lipid and carbohydrate homeostasis by altering mitochondrial matrix iron metabolism. Here we determine the key transcriptional events in subcutaneous WAT of mice in response to mitoNEET overexpression and a high-fat diet (HFD). Microarray analyses at key points during weight gain upon body weight divergence with wild-type mice demonstrate that mitoNEET-enriched sWAT early on, upregulates a browning signature programme that limits WAT expansion in transgenic mice for a period of up to 12 weeks of HFD. This compensatory browning phenotype is subsequently lost, resulting in rapid WAT expansion and body weight gain. Exposure to thermoneutral temperatures during HFD prompts weight gain significantly earlier. Similar WAT expansion is achieved upon infection with an adeno-associated virus expressing mitoNEET. Collectively, the mitoNEET-enriched fat pads feature a more vascularized, anti-inflammatory and less fibrotic environment.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor (FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD.

Sepsis hyperglycemia is poorly understood. It is not known whether there is a role in sepsis hyperglycemia for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), crucial for normal glucose metabolism. We developed an in vitro model of sepsis employing monocytes (crucial cells in mediating sepsis) and hepatocytes (crucial cells in carbohydrate homeostasis) to clarify the role of the incretin system in sepsis.

Predictable and well-recognized physiologic and metabolic alterations occur in response to trauma, sepsis or surgery. The major posttraumatic effects are: increased metabolic rate, protein breakdown, negative nitrogen balance, and alteration of the carbohydrate homeostasis, including elevated blood glucose concentration, increased endogenous glucose production, elevated insulin levels and insulin resistance.

The fetus is completely dependent on mother for glucose and other nutrient transfer across the placenta. At birth, when the maternal supply is discontinued, the neonate must adjust to an independent existence. The changes in the neonate's glucose homeostasis during this transition to the extrauterine environment are influenced by the mother's metabolism and intrinsic fetal and placental problems. Maturation of carbohydrate homeostasis results from a balance between substrate availability and coordination of developing hormonal, enzymatic, and neural systems. These mechanisms may not be fully developed in neonates, so the neonate is vulnerable to carbohydrate disequilibrium resulting in damage to the central nervous system. Hypoglycemia is a relatively common metabolic problem seen during newborn care. However its definition, management and long term sequalae remain controversial. Hyporglycemia occurs frequently as a transient disorder with excellent prognosis. It also may persist and recur and cause permanent neurological complications. Although the key to effective treatment of hypoglycemia is diagnostic specific, the maintenance of euglycemia is critical to the preservation of central nervous system function. This article discusses physiology of perinatal glucose homeostasis, focusing on evaluation and treatment of hypoglycemia.

On the basis of the inhibitory actions of the somatostatin analogue SMS 201-995 on growth hormone (GH) and glucagon (IRG) secretion we investigated its effects on carbohydrate metabolism of insulin-dependent diabetics. Six patients with no residual insulin secretion were connected to the artificial endocrine pancreas (AEP) and after the establishment of a steady state overnight they were injected either normal saline or 50 micrograms of SMS 201-995 s.c., t.i.d., or 100 micrograms of the same compound b.i.d. Insulin requirements were assessed by the AEP and compared during the 24 h and after the main meals. The inhibition of GH and IRG secretion was evaluated as well. 50 micrograms of SMS analogue t.i.d. induced a significant reduction of insulin requirement (mean +/- SEM) while no significant difference was observed between control and 100 micrograms s.c., b.i.d., nor between 50 micrograms and 100 micrograms. The curve of glucose fluctuations was smoother after 50 micrograms than after 100 micrograms and control. Postprandial IRG secretion was inhibited by both regimens of SMS after lunch and dinner. GH secretion was significantly inhibited after all meals during the days of analogue administration. SMS 201-995 analogue appears to have a remarkable antidiabetic activity as shown by the sparing of administered amount of insulin, suppression of counter-insulin hormones and smoothing of blood glucose curve. It may constitute a safe and effective adjunctive measure in the management of insulin-dependent diabetics.

Altered carbohydrate metabolism has been reported during episodes of neo natal infection. To document that there is more rapid glucose disappearance during infection, intravenous glucose tolerance tests (IVGTT) and serial plasma growth hormone and insulin levels were determined in eight full-term neonates during the first three days of an acute episode of infection and during convalescence, 5 to 15 days later. Eight healthy infants were each studied once using the same study protocol. Glucose disappearance rates, measured as Kt of glucose, were increased (p < 0.01) during both the acute septic period (3.7 ± 0.3% disappearance/min; mean ± S.E.M.) and convalescent period (2.5 ± 0.2%/min) when compared with values in control infants (1.3 ± 0.3%/min). Gram-negative, gram-positive, and viral infections were all associated with rapid glucose disposal. The ab normality in carbohydrate homeostasis persisted for at least 5 to 15 days after treatment was begun. Baseline and stimulated (20-minutes post bolus glucose infusion) plasma insulin and growth hormone levels did not differ among the groups. Thus, there is no evidence that hyperinsulinism produced the rapid glucose disappearance rate and enhanced glucose utilization. The reason for the disturbed carbohydrate metabolism in neonatal infections remains un known.

In an attempt to differentiate the effect of fenfluramine hydrochloride from that of caloric restriction on carbohydrate tolerance in patients with lipodystrophy, parameters of carbohydrate homeostasis were studied in patients with lipodystrophy during periods offenfluramine treatment and during periods of caloric restriction. Although carbohydrate tolerance appeared to improve initially in one patient when treated with fenfluramine, this improvement did not persist. No beneficial influence of fenfluramine on carbohydrate tolerance could be identified in the other patients studied. By contrast, all patients demonstrated an improvement in carbohydrate tolerance in response to caloric restriction. These data suggest that caloric restriction improves carbohydrate tolerance in patients with lipodystrophy whereas fenfluramine, in the absence of caloric restriction, has no long-term beneficial effect.

Increased understanding of maternal-fetal carbohydrate homeostasis together with modern perinatal technology now provides a more rational basis for obstetric management of the pregnant diabetic patient. These concepts were applied at MacDonald House in the care of 96 diabetic pregnant women over a two-year period. Pregnancy outcomes were compared with prior experiences with the same group of women. The perinatal mortality rate was reduced from 13.5 to 4.2%, and the rate of macrosomia (infants large for gestational age) was reduced from 30.9 to 17.7%. Patients with gestational diabetes, with a prior loss rate of 8.3%, suffered no losses in the current series. Maternal age was not found to correlate with an untoward outcome in this subgroup.

Somatostatin, a peptide inhibitor of growth hormone release originally isolated from the hypothalamus, is also present in D cells of pancreatic islets. Its ability to inhibit the secretion of insulin and glucagon suggests that it may be a local regulator of pancreatic A- and B-cell function. Studies using synthetic somatostatin have provided evidence that glucagon is a physiologically important hormone that exacerbates the consequences of insulin deficiency in human diabetes mellitus. The ability of somatostatin to diminish both fasting and postprandial hyperglycemia and to forestall the development of ketoacidosis after withdrawal of insulin in insulin-dependent diabetics suggests a potential therapeutic use of this agent in diabetes. Presently, however, its short half-life and diverse actions preclude such use and have prompted the search for more specific and longer-acting analogs. ( Arch Intern Med 137:659-666, 1977)

Normalization of plasma glucose concentration with subcutaneous injections of insulin has been difficult. With intravenous insulin delivery, normalization of plasma glucose concentration in adult-onset diabetic patients has been achieved when their plasma insulin concentration was normalized. In juvenile-onset diabetic subjects totally lacking endogenous insulin, the effect of normalization of the plasma insulin concentration has not yet been reported. In the present studies, the plasma insulin profile was normalized in four brittle, insulin-dependent diabetic subjects throughout three meals (breakfast, lunch, and supper). Plasma free insulin concentration was assayed after precipitation of endogenous insulin antibodies with polyethylene glycol. Acute meal-related increases in plasma free insulin concentration were achieved with a programmable intravenous insulin delivery system. When plasma insulin profiles were normalized in insulin-dependent diabetic subjects lacking endogenous insulin secretion, an improvement in meal-related glucose excursions was observed. However, complete normalization of plasma glucose concentration was not achieved, suggesting that factors other than plasma insulin concentration modulate carbohydrate homeostasis in brittle diabetes. These factors may include portal vein hypoinsulinemia during peripheral vein insulin infusion, stress hormone concentrations, and tissue insulin resistance.

1. Experiments were carried out to establish what relationship there is between the concentration of ketone bodies in the blood and the concentrations of glycogen in muscle and liver of thirty-six trained and thirty-six untrained rats exercised at the same absolute load. There were, in addition, non-exercised control animals (of which thirty-six were trained and thirty-six untrained) which were studied on the same day. 2. Training occurred on a level treadmill at 0.2 m/s for 1 h/day, 5 days a week, for 6 weeks. The untrained animals ran on the treadmill every 3rd day for 5 min to maintain familiarity with treadmill running without training them. 3. At the end of the 6th week, the experimental animals ran for 1 h at 0.2 m/s on a level treadmill. Blood 3-hydroxybutyrate and tissue glycogen concentrations were measured at the beginning and immediately after exercise, and then every 30 min for 2 h. 4. Physically trained rats had higher pre- and immediate post-exercise liver glycogen concentrations than untrained rats: 413 +/- 15 and 300 +/- 8 mumol/g before exercise in trained and untrained rats respectively, and 225 +/- 8 and 166 +/- 3 mumol/g immediately after (P less than 0.05). 5. Muscle glycogen, which was also higher in trained than in untrained rats, was resynthesized at approximately the same rate in the two groups of animals (9 and 11 mumol/(g h), but the trained animals were able to achieve this without further depletion of liver glycogen beyond that which had occurred during exercise. In untrained animals liver glycogen concentrations continued to drop for 60 min beyond the end of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Based on the known action of xanthine derivatives on the insulin secretion, the effect of pentoxifylline on carbohydrate homeostasis of type I (IDDM) and type II (NIDDM) diabetics was investigated. Pentoxifylline is known to exert a favorable influence on hemorheological disturbances in such patients. Twenty-four hour blood glucose pattern and insulin requirements were evaluated in type I and type II diabetics by the use of the artificial pancreas before and after a 14-day treatment with pentoxifylline 400 mg p.o. (Trental 400) t.i.d. During the stabilization period before treatment with pentoxifylline, NIDDM patients required 10.1 +/- 3.8 U of insulin and the IDDM 35 +/- 13.7 U. After 2 weeks on pentoxifylline, NIDDM required only 6.3 +/- 2.8 U (p less than 0.05) and IDDM 28.5 +/- 9.7 U (n.s.). Average blood glucose during the 24h decreased by 15.8 +/- 3.5% in NIDDM and by 10.3 +/- 2.5% in IDDM. Moreover, a significant smoothing of glucose fluctuations during the 24h was noted in both groups. It is concluded that pentoxifylline administered concurrently to any antidiabetic type of treatment leads to better blood glucose control as well as to prevention or delay of vascular complications.

Najjar, S., Salem, G. and Idriss, Z. (Department of Pediatrics, The American University of Beirut, Beirut, Lebanon). Congenital generalized lipodystrophy. Acta Paediatr Scand, 64:273, 1975.–Six patients with congenital generalized lipodystrophy are described. They had generalized paucity of fat tissue, acanthosis nigricans, prominent superficial veins and muscle hypertrophy. They were mentally retarded. Three had corneal opacities. They had normal external genitalia and none was tall for age. Their bone age was advanced and some had minor skeletal anomalies and nephromegaly. The muscle histology on light microscopy was normal. The majority had elevated serum aldolase and to a lesser degree serum lactic dehydrogenase and creatinine phosphokinase. Four of five examined had a myopathic electromyogram. They had normal or minimally deranged liver function tests. The fatty liver infiltration in one seems to be progressive. Four had a normal and two an abnormal metyrapone test. They had an age-dependent abnormality of growth hormone, insulin and carbohydrate homeostasis.

Patients with nonketotic diabetes mellitus, who were both obese and had significant fasting hyperglycemia (mean plasma glucose = 310 mg/100 ml), were fasted for 10 days. There was a prompt drop of plasma glucose levels as the result of the caloric deprivation with a mean fall of approximately 200 mg/dl at the end of the fast. The drop in plasma glucose level that occurred during the fast was associated with a drop in plasma insulin level. Fasting plasma glucose concentration rose immediately after food intake was resumed and stabilized within 3--4 days at levels halfway between the initial and the lowest value. At this time, the patients also seemed capable of disposing of an oral glucose load more efficiently. The apparent improvement in carbohydrate homeostasis observed after the fast could not be attributed to an increase in insulin response, but was associated with some amelioration of the insulin resistance that characterizes these patients. Unfortunately, the beneficial effects of the 10-day period of caloric deprivation were transitory and fasting plasma glucose values had returned to prefast levels in most patients within a few months.

Carbohydrate homeostasis was evaluated in 47 girls with Turner syndrome and in 25 "short normal" girls by means of an oral glucose tolerance test. Of the Turner patients 34% showed an impaired glucose tolerance vs 8% of the controls (chi 2 = 5.9, P less than 0.05). Mean glucose levels were significantly higher and mean insulin levels and insulinogenic index significantly lower in young Turner patients aged 5-12 years but not in adolescents aged 12-16 years. In both groups of patients, insulin levels and the insulinogenic index were significantly lower than those of the controls. In Turner patients between 12 and 16 years, carbohydrate tolerance improved and this may be explained by the lack of oestrogen release in these patients. Glucose tolerance was normal in patients with mosaicism. We conclude that (1) carbohydrate tolerance is defective in young children with Turner syndrome but improves in puberty due to the almost complete absence of oestrogen-progestogen secretion; (2) a difference in carbohydrate tolerance is evident depending on karyotype.

To investigate the effect of ethanol on carbohydrate homeostasis in circumstances in which food and ethanol are usually ingested, ethanol was administered hourly in the afternoon prior to the ingestion of a glucose load at 5:00 p.m. in a group of normal subjects and in mild diabetics. In both groups the blood glucose levels following the glucose load were 30–80 mg 100 ml lower and the early insulin secretory response (15–45 min) was 35%–40% higher after ethanol ingestion. In contrast, ethanol intake had no effect on the glucagon response to glucose ingestion. These data suggest that ethanol enhances glucose-stimulated insulin secretion. The dampened blood glucose rise observed with ethanol may be related to the augmented insulin response or to decreased gastrointestinal absorption of glucose. In mild diabetic patients, moderate intake of ethanol is without acute deleterious effects on carbohydrate homeostasis and may in some instances improve the blood glucose response to ingested carbohydrate.