Chemoreactomic analysis of inositol stereoisomers: different profiles of pharmacological activity of myo-inositol and D-chiro-inositol in females with reproductive system disorders

Inositol-containing drugs (stereoisomers of cyclohexane-1,2,3,4,5,6-hexol) are used to compensate insulin resistance, particularly in patients with menstrual and ovarian disorders. Inositols are effective in preventing folate-resistant fetal malformations. Objective. To analyze pharmacological differences between the four main biologically active stereoisomers of inositol: myoinositol (MI), D-chiro-inositol (DCI), neo-inositol (NI), and scylloinositol (SCI) using the comparative chemoreactomic method. Materials and methods. Chemoreactom analysis, PubChem / PHARMGKBb HMDB, STRING databases Results. DCI is more sufficient than MI for (1) processing of branched-chain amino acids, which promotes normalization of glucose metabolism, as well as (2) metabolism of folates, vitamin PP, vitamin B5, and magnesium, (3) activation of insulin-like growth factor 1 (IGF-1) receptor, whose activity is important for the prevention of sarcopenia, (4) antitumor effects (by inhibiting hyperproliferative effects, including those associated with excess glucose and an imbalance of androgens and estrogens), (5) inhibition of proinflammatory proteins (matrix metalloproteinase 15, ICAM1, and IRAK4 that mediate effects of interleukin-1). Conclusion. The profiles of pharmacological activity of DCI and SCI differ significantly from those of MI and NI. Therefore, combinations of MI and DCI are a more promising option to increase the sensitivity of cells to insulin than separate use of MI or DCI. Key words: insulin resistance, hyperandrogenism, polycystic ovary syndrome, post-genomic pharmacology, myo-inositol, D-chiro-inositol, neo-inositol, scylloinositol, Dikirogen

The Treatment and Natural Course of “Insulin Neuritis” or Treatment-induced Neuropathy from the Perspective of 2 Cases

“Insulin neuritis” or “treatment-induced neuropathy” is a relatively rare disease course after the adequate regulation of glucose levels by insulin in diabetes mellitus. In 1933 the syndrome was first described. Typically, the onset of pain, presenting as polyneuropathy, is just after the start of the (adequate) treatment for diabetes mellitus. In this article we present 2 cases (both women, 15 and 22 years of age) with a course such as was described in 1933. They were treated with oral gabapentin, pregabalin, amitriptyline, duloxetine, tramadol and with transdermal capsaicin 8% patch. Simultaneously, glucose levels were carefully monitored and diabetes mellitus and comorbidities (mainly ocular and gastro-intestinal) were treated. Treatment effects were variable, and patients seemed to show some spontaneous/ natural recovery of complaints. Furthermore, we describe the pathophysiology, diagnosis, therapy, and natural course. “Insulin neuritis” or “treatment-induced neuropathy” is pain in polyneuropathy with a (sub)acute onset after adequate glycemic control of diabetes mellitus with insulin, whereby traditionally this is seen as one of the mainstays in the treatment for polyneuropathy in diabetes mellitus. Possibly this is due to ectopic generation of impulses in regenerating axons. From the limited literature, it follows that the course is variable, but that spontaneous remission of pain is possible, especially after 18 months of adequate glycemic control. There are no separate treatment strategies described in this form or genesis of pain in polyneuropathy, other than that which could be derived from the treatment of other forms of pain in polyneuropathy. Key words: Insulin neuritis, treatment induced neuropathy, polyneuropathy, transdermal capsaicin, diabetes mellitus

INSULIN RESISTANCE IN PATIENTS WITH CONGESTIVE HEART FAILURE

Objects: To identify insulin resistance in patients with congestive heart failure and evaluated the association between insulin resistance with NYHA functional classification, EF and serum NTprpBNP level. Patients and Methods: 30 patients with congestive heart failure were assessed the NYHA functional classification and measured the concentration of NTproBNP, fasting plasma of insulin and glucose. The HOMA index; QUICKI index and I0/G0 were evaluated for insulin resistance. Results: The plasma concentration of I0 was 5,4±1,24 µU/ml. The values of I0/G0 index was 1,15±1,03, HOMA index was 1,53±1,3 and QUICKI index was 0,39±0,07. The prevalence of insulin resistance in congestive heart failure patients presented respectively from 43% to 100% basing on HOMA index and QUICKI index.There were significantly correlation between HOMA index and NYHA functional classification (r=0,502, p<0,001), NT-proBNP concentration (r=0,69, p<0,001), and EF index (r= -0,75, p<0,001). There were significantly correlation between QUICKI index with NYHA functional classification (r= - 0,407, p<0,05), NT-proBNP levels (r= - 0,7, p<0,001) and EF index (r= 0,58, p<0,001). Conclusions: Insulin-resistance was present high prevalence in patients with congestive heart failure in which there were correlation between insulin resistance with EF and NTproBNP. Key Words: Insulin resistance, heart failure

The effects of the insulin-like growth factor-I aptamer, NBI-31772, on glucose homeostasis in the mouse

The majority of insulin-like growth factor-I (IGF-I) in the adult rodent circulation is bound to high affinity IGF binding proteins. We investigated the changes in IGF-I clearance, blood glucose and plasma insulin levels, and tissue 2-deoxyglucose uptake after intravenous administration of the IGF aptamer, NBI-31772, which selectively competes with IGF-I for binding to the IGFBPs, but has no effect at the IGF-I receptor. Clearance of 125I-IGF-I was significantly increased in NBI-31772-treated mice compared with vehicle-treated mice (t1/2 = 45.0 ± 1.9 vs. 56.3 ± 3.9 min, respectively; p = 0.021). However, NBI-31772 had no significant effect on glucose levels, and no insulin sparing effect was apparent neither under basal conditions nor during an intravenous glucose challenge. The decline in the specific activity after 3H-2-deoxyglucose administration was significantly less rapid in NBI-31772-treated mice compared with controls, suggesting that the IGF-I aptamer had an inhibitory effect on hepatic gluconeogenesis. In contrast, no insulin-like effect was apparent in other tissues examined. 3H-2-deoxyglucose accumulation was similar in all tissues analyzed, including skeletal muscle, which is thought to be particularly sensitive to IGF-I. These data suggest that the IGF-I aptamer affects clearance of radiolabeled IGF-I from the circulation, but has no marked effects on glucose nor insulin homeostasis. The search for hydrophilic IGF aptamers with longer duration of action that could be used in the treatment of diabetes may be rewarding. Key words: insulin resistance, gluconeogenesis, 2-deoxyglucose uptake, glucose clearance.

Insulin Sensitivity in Skeletal Muscle Regulated by a Hepatic Hormone, HISS

The current state of the HISS (hepatic insulin sensitizing substance) hypothesis is briefly outlined. In the postmeal absorptive state, 50-60% of the glucose storage action of insulin is accounted for by the actions of HISS released from the liver and acting on skeletal muscle. Hepatic parasympathetic nerves permissively regulate the ability of a pulse of insulin to release HISS, thereby potentiating the impact of insulin in the fed state. HISS release in response to insulin decreases progressively with fasting to create a physiological state of HISS-dependent insulin resistance. HISS release is regulated by parasympathetic nerves via muscarinic receptors and nitric oxide, and insulin resistance of skeletal muscle produced by hepatic denervation is reversed by intraportal but not intravenous acetylcholine or a nitric oxide donor. It is suggested that HISS-dependent insulin resistance occurs in animal models including sucrose-fed rats, spontaneously hypertensive rats, chronic liver disease, fetal alcohol effect in the adult offspring, and type 2 diabetes. Key words: insulin resistance, RIST, parasympathetic nerves, liver, diabetes

Metabolic Syndrome, a Cardiovascular Disease Risk Factor: Role of Adipocytokines and Impact of Diet and Physical Activity

The metabolic syndrome comprises an array of cardiovascular disease (CVD) risk factors such as abdominal obesity, dyslipidemia, hypertension, and glucose intolerance. Insulin resistance and/or increased abdominal (visceral) obesity have been suggested as potential etiological factors. More recently, increasing evidence has associated insulin resistance and subclinical inflammation involving cytokines derived from adipose tissue, or adipocytokines. Despite the fact that precise mechanisms have yet to be established, there is a significant role for both diet and physical activity to improve the many factors associated with the metabolic syndrome, including modulation of various adipocytokines. Although both diet and physical activity have been studied for their ability to modify cytokines in more traditional inflammatory conditions, such as rheumatoid arthritis, they have been less studied in relation to inflammation as an underlying cause of the metabolic syndrome and/or CVD. A more thorough understanding of the clustering of metabolic abnormalities and their underlying etiology will help to define diet and physical activity guidelines for preventing and treating the metabolic syndrome, an important aspect of CVD prevention. This paper will address potential underlying causes of the metabolic syndrome, with a focus on the putative mechanistic role of adipocytokines, and will discuss the impact of diet and physical activity on the metabolic syndrome. Key words: insulin resistance syndrome, obesity, adipose tissue, skeletal muscle, cytokines, TNF-α, IL-6, PAI-1, inflammation, nutrition, exercise

Dietary Carbohydrate and its Effects on Metabolism and Substrate Stores in Sedentary and Active Individuals

This review of carbohydrate (CHO) ingestion and exercise addresses three major issues: (a) how CHO ingestion influences CHO and fat stores, (b) how exercise, by changing CHO stores, alters the responses to CHO or fat ingestion, and (c) the roles of CHO in exercise performance and metabolism. Dietary manipulation is not a simple issue; increasing the dietary content of any specific nutrient alters the entire diet composition. High CHO diets are often low fat diets, hence changing the metabolism and storage of both fat and CHO. Acute CHO ingestion increases CHO oxidation and the "spared" fats are deposited as fat. Chronic high CHO ingestion (without an active lifestyle) leads to muscle becoming insulin-insensitive, adipose tissue processing CHO to fatty acids, and the liver increasing production of VLDL triglycerides. CHO ingestion prior to and during prolonged exercise can increase endurance. It has been suggested that moderate or low glycemic index forms be used prior to and during the exercise, but there is no consensus as to whether it should be a recommendation. The physiological nature of the regulation of CHO stores is poorly understood, but the recent identification of a key enzyme, glycogenin, and two forms of glycogen (pro- and macroglycogen) show promise of a deeper understanding. Key words: insulin, glycogen, triglyceride, liver, adipose tissue, de novo lipogenesis

Insulin and glucagon responses to intravenous injections of glucose, arginine and propionate in lactating cows and growing calves

Plasma insulin and glucagon responses to glucose, arginine and propionate injections were measured to establish indicators of the endocrine status in lactating cows and growing calves. The metabolites were intravenously injected at a dose of 0.625 mmol kg−1 and the time courses of changes in plasma insulin and glucagon concentrations were determined. Basal plasma glucagon concentrations were higher (P < 0.05) for lactating cows than for growing calves, while basal plasma insulin concentrations did not differ between animal groups. Concentrations of plasma insulin increased (P < 0.01) after glucose injection, whereas plasma glucagon concentrations decreased in both lactating cows (P < 0.05) and growing calves (P < 0.01). Plasma insulin and glucagon concentrations increased in response to arginine (P < 0.01) and propionate (P < 0.01 except insulin for lactating cows at P < 0.05) injections. Plasma insulin and glucagon responses were greater (P < 0.05) to arginine than to glucose or propionate. Plasma glucagon responses to arginine were greater (P < 0.05) for lactating cows than for growing calves. The insulin:glucagon molar ratio increased in response to the metabolite injections except following injections of arginine and propionate into lactating cows, when the ratio did not increase significantly. It is possible that in cows the enhanced responsiveness of glucagon secretion plays a role in the maintenance of lactation. Key words: Insulin, glucagon, arginine, propionate, lactating cow, growing calf

Metabolic and Hormonal Responses to Exercise in Partially Hepatectomised Rats

To characterise how the liver affects metabolic and hormonal exercise responses, hepatectomised (70%; HX) rats were submitted to a 30- or 50-min treadmill exercise (26 m/min, 0% slope) 48 hr or 7 days after surgery (reduced or normal liver mass, respectively). To determine whether metabolic effects of liver mass reduction during exercise were caused by reduced capacity of the liver to produce glucose, metabolic and hormonal responses to the same exercise protocol were measured in 48-hr HX rats. Euglycemia, maintained by exogenous glucose infusion, produced attenuated lactate, insulin, and glucagon values in 48-hr HX rats but did not affect FFA, glycerol, and plasma catecholamine responses. Results indicate that metabolic and hormonal exercise responses are amplified in 48-hr HX rats. Maintaining euglycemia in 48-hr HX rats during exercise does not reduce all responses. Intrahepatic events, similar to those in a short-term (48-hr) HX liver, may influence metabolic and hormonal exercise responses. Key words: insulin, glucagon, catecholamines, glycemia, hepatectomy, hepatic receptors

A comparison of changes in whole body and skin amino acid metabolism of sheep in response to 24 h continuous infusions of variants of insulin-like growth factor 1

Because of the economic significance of wool to many sheep production systems, attempts to partition amino acids towards skin and wool protein synthesis have included both nutritional and hormonal methods of manipulation. A variant of insulin-like growth factor 1 (IGF-1) has previously been shown to transiently increase protein synthesis in the skin of sheep and the current study extended that work by comparing the effects of a 24 h, close-arterial, skin infusion of IGF-1, in the form of either recombinant human (rhIGF-1) or an extended variant (LR3IGF-1), on both whole body and skin amino acid metabolism adult, castrated Romney sheep, with three animals allocated to each treatment. There were no differences in food intake between the two treatment groups. The plasma concentration of immunoreactive IGF-1 of sheep infused with rhIGF-1 increased (P < 0.01) with time of administration, but decreased (P < 0.05) after 24 h of LR3IGF-1 infusion. Administration of both IGF-1 variants caused a substantial and sustained decrease in arterial insulin to less than 50% (P < 0.05) of pre-infusion values, while arterial plasma glucose concentrations were only reduced by 7%. Alterations in whole body and skin protein metabolism were assessed from continuous infusions of mixed [U-13C] AA, [2,6 ring 3H]phenylalanine and [35S]cysteine. Within 4 h both AA concentrations and whole body plasma ILR of essential and non-essential AA were decreased (P < 0.05 for seven AA) by IGF-1 infusions. Both IGF1 variants caused acute increases (P < 0.05) in skin blood flow and, for 13 of the 15 AA measured, isotopic transfers (range 50–220%; P < 0.05 for cysteine and tyrosine), which probably reflect increased protein synthesis. By 24 h skin blood flow, AA uptake and protein synthesis had returned to pre-infusion values. Strategies based on exogenous application, or enhanced endogenous production, of IGF-1 are unlikely, therefore, to produce persistent anabolic responses. Key words: Insulin-like growth factor 1, skin, sheep, protein synthesis