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Cycloferin is an extract of the chemicals from the Cyclopia species, which grows only in small areas in the southwest and southeast of South Africa and has been consumed traditionally as a nourishing tea to treat numerous health issues and illnesses. Previous studies report that some of the active compounds in Cycloferin, such as pinitol (a modified sugar) and mangiferin (a glucoside), may reduce blood sugar levels and therefore may be used as a treatment for diabetes. Mangiferin, in particular, has been shown to stimulate carbohydrate oxidation and alleviate some effects of insulin resistance and hyperglycemia. Other active components of Cycloferin include flavones, isoflavones, coumestans, luteolin, 4-hydroxycinnamic acid, polyphenols, and xanthones. These active compounds are antioxidants, which can enhance glucose breakdown, lower blood lipids, and reduce the number of highly reactive compounds known as free radicals, which can alter cellular structure and function when present in large amounts. In this study, we explored the ameliorative effects of Cycloferin by treating streptozotocin- (STZ) injected rats with Cycloferin and evaluating its long-term and short-term effect on blood glucose levels and kidney and liver conditions of the diabetic-rendered rats. Our results demonstrated the ability of Cycloferin to both lower the blood glucose levels and reduce evidence of damage in kidney and liver in diabetic rats with and without exogenous insulin treatment for partial control of diabetic state.

Diabetes mellitus, as a result of microvascular and macrovascular injury, causes organ dysfunction in a wide variety of tissues. The objective of this study was to investigate the effect of combined inositol hexakisphosphate and inositol supplement on renal and pancreatic integrity in type 2 diabetic rats. Thirty male Sprague-Dawley rats were divided into five groups (n=6 per group). Type 2 diabetes was induced in three groups using high-fat diet combined with a single dose of streptozotocin (35mg/kg body weight, intraperitoneally). Two of the diabetic groups were treated with combined IP6 and inositol or glibenclamide. Serum biochemical markers of kidney damage kidney, antioxidant status (superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) and lipid peroxidation were measured. Histomorphological and morphometric examinations of the H&E stained pancreas were also carried out. The administration of combined IP6 and inositol supplement resulted in 64% and 27% increase in CAT activities and GSH levels respectively and a 25% decrease in lipid peroxidation level compared to the diabetic control. Serum uric acid, creatinine and BUN levels in the combination treated group was comparable to the normal control. Examination of H&E stained pancreatic sections showed a significant increase (107%) in the number of islets in the combined IP6 and inositol treated group compared to the untreated diabetic group. Overall, the treatment of type 2 diabetic rats with combined IP6 and inositol supplement resulted in the improvement of renal and pancreatic function., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Mimosa pudica Linn. (Mimosaceae) has been traditionally used for the management of type 2 diabetes mellitus (T2DM) in India. The present study evaluates the therapeutic efficacy of myoinositol (25 and 50mg/kg) isolated from M. pudica stem methanol extract in Triton WR-1339 induced hyperlipidemic and high-fat diet (HFD) fed-streptozotocin (STZ)-induced insulin-resistant diabetic rats. Lipid biomarkers, fasting blood glucose (FBG), changes in body weight, food and water intakes, plasma insulin, HOMA-IR, oral glucose tolerance, intraperitoneal insulin tolerance, urea, creatinine, marker enzymes of liver function, β-cell function and the expression levels of insulin receptor-induced signaling molecules were studied. Molecular-docking was also carried out to determine the possible interactions of myoinositol into the active sites of insulin-induced signaling markers. In addition, histology of liver, pancreas, kidney, heart and adipose tissues were also performed. In Triton WR-1339 induced hyperlipidemic rats, myoinositol (25 and 50mg/kg) exhibited significant reductions in total cholesterol: 37.5% and 59.73%, triglycerides: 57.75% and 80.14% and LDL-c: 81.44% and 101.75% respectively. HFD fed-STZ receiving myoinositol (25 and 50mg/kg) showed significant reductions in fasting blood glucose: 55.68% and 56.48%, plasma insulin level: 25.45% and 27.06% when compared with diabetic control. It significantly normalized the hyperglycemia induced biochemical abnormalities in insulin-resistant diabetic rats. Furthermore, it demonstrated cytoprotective effects besides increase in the intensity of positive reaction for insulin in pancreas. Myoinositol enhanced the level of PPARγ expression in the adipose tissue of treated rats when compared with rats that did not receive drug treatment; also, it significantly upregulated GLUT4 and IR signaling molecules. Myoinositol had predicted the interactions within the active sites of PPARγ, GLUT4 and IR. These findings suggested that myoinositol could play an effective role in glucose disposal into adipose tissue by insulin-dependent signaling cascade mechanism; hence it could be used in the treatment of obesity-associated T2DM., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Gestational diabetes mellitus (GDM) is a growing concern, affecting an increasing number of pregnant women worldwide. By predisposing both the affected mothers and children to future disease, GDM contributes to an intergenerational cycle of obesity and diabetes. In order to stop this cycle, safe and effective treatments for GDM are required. This study sought to determine the treatment effects of dietary supplementation with myo-inositol (MI) and vitamins B2, B6, B12, and D in a mouse model of GDM (pregnant db/+ dams). In addition, the individual effects of vitamin B2 were examined. Suboptimal B2 increased body weight and fat deposition, decreased GLUT4 adipose tissue expression, and increased expression of inflammatory markers. MI supplementation reduced weight and fat deposition, and reduced expression of inflammatory markers in adipose tissue of mice on suboptimal B2. MI also significantly reduced the hyperleptinemia observed in db/+ mice, when combined with supplemented B2. MI was generally associated with adipose tissue markers of improved insulin sensitivity and glucose uptake, while the combination of vitamins B2, B6, B12, and D was associated with a reduction in adipose inflammatory marker expression. These results suggest that supplementation with MI and vitamin B2 could be beneficial for the treatment/prevention of GDM.

Insulin-mimetic species of low molecular weight are speculated to mediate some intracellular insulin actions. These inositol glycans, which are generated upon insulin stimulation from glycosylphosphatidylinositols, might control the activity of a multitude of insulin effector enzymes. Acylated inositol glycans (AIGs) are generated by cleavage of protein-free GPI precursors through the action of GPI-specific phospholipase C (GPI-PLC) and D (GPI-PLD). We synthesized AIGs (IG-1, IG-2, IG-13, IG-14, and IG-15) and then evaluated their insulin-mimicking bioactivities. IG-1 significantly stimulated glycogen synthesis and lipogenesis in 3T3-L1 adipocytes and rat isolated adipocytes dose-dependently. IG-2 significantly stimulated lipogenesis in rat isolated adipocytes dose-dependently. IG-15 also enhanced glycogen synthesis and lipogenesis in 3T3-L1 adipocytes. The administration of IG-1 decreased plasma glucose, increased glycogen content in liver and skeletal muscles and improved glucose tolerance in C57B6N mice with normal diets. The administration of IG-1 decreased plasma glucose in STZ-diabetic C57B6N mice. The treatment of IG-1 decreased plasma glucose, increased glycogen content in liver and skeletal muscles and improved glucose tolerance in C57B6N mice with high fat-diets and db/db mice. The long-term treatment of IG-1 decreased plasma glucose and reduced food intake and body weight in C57B6N mice with high fat-diets and ob/ob mice. Thus, IG-1 has insulin-mimicking bioactivities and improves glucose tolerance in mice models of diabetes with or without obesity.

Aim: D-chiro-inositol (DCI) has been shown to prevent and reverse endothelial dysfunction in diabetic rats and rabbits. The present study evaluates the preventive effect of DCI on experimental diabetic neuropathy (DN)., Methods: Streptozotocin-induced (STZ) diabetic mice were treated by oral gavage for 60 days with DCI (20 mg/kg/12 h) or saline (NaCl 0.9%; 0.1 ml/10 g/12 h; Diab) and compared with euglycaemic groups treated with saline (0.1 ml/10 g/12 h; Eugly). We compared the response of the isolated sciatic nerve, corpora cavernosa or vas deferens to electrical stimulation., Results: The electrically evoked compound action potential of the sciatic nerve was greatly blunted by diabetes. The peak-to-peak amplitude (PPA) was decreased from 3.24 ± 0.7 to 0.9 ± 0.2 mV (p < 0.05), the conduction velocity (CV) of the first component was reduced from 46.78 ± 4.5 to 26.69 ± 3.8 ms (p < 0.05) and chronaxy was increased from 60.43 ± 1.9 to 69.67 ± 1.4 ms (p < 0.05). These parameters were improved in nerves from DCI-treated mice (p < 0.05). PPA in the DCI group was 5.79 ± 0.8 mV (vs. 0.9 ± 0.2 mV-Diab; p < 0.05) and CV was 45.91 ± 3.6 ms (vs. 26.69 ± 3.8 ms-Diab; p < 0.05). Maximal relaxation of the corpus cavernosum evoked by electrical stimulation (2-64 Hz) in the Diab group was 36.4 ± 3.8% compared to 65.4 ± 2.8% in Eugly and 59.3 ± 5.5% in the DCI group (p < 0.05). Maximal contraction obtained in the vas deferens was 38.0 ± 9.2% in Eugly and 11.5 ± 2.6% in Diab (decrease of 69.7%; p < 0.05), compared to 25.2 ± 2.3% in the DCI group (p < 0.05 vs. diabetic). Electron microscopy of the sciatic nerves showed prevention of neuronal damage., Conclusions: DCI has a neuroprotective action in both autonomic and somatic nerves in STZ-induced DN., (© 2011 Blackwell Publishing Ltd.)

Aim: Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and voglibose, an alpha-glucosidase inhibitor, have different but complementary mechanisms of action on glucagon-like peptide-1 (GLP-1) regulation and glucose-lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice., Methods: Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice., Results: After 3 weeks, voglibose treatment increased GLP-1 secretion (voglibose alone, 1.6-fold; alogliptin plus voglibose, 1.5-fold), while it decreased plasma glucose-dependent insulinotropic polypeptide (GIP) (voglibose alone, -30%; alogliptin plus voglibose, -29%). Alogliptin, voglibose and combination treatment decreased plasma DPP-4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP-1 levels by 4.5-, 1.8- and synergistically by 9.1-fold respectively. Combination treatment increased plasma insulin by 3.6-fold (alogliptin alone, 1.3-fold; voglibose alone, 1.8-fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6-, 3.4- and synergistically by 8.5-fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha-cell distribution in the pancreatic islet., Conclusions: Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP-1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta-cells and islet structure in prediabetic db/db mice.

During diabetes mellitus, endogenous hepatic glucose production is increased as a result of impaired activities of the key enzymes of carbohydrate metabolism, which leads to the condition known as hyperglycemia. D-pinitol, a bioactive constituent isolated from soybeans, has been shown to reduce hyperglycemia in experimental diabetes. We therefore designed this study to investigate the effect of oral administration of D-pinitol (50 mg/kg b. w. for 30 days) on the activities of key enzymes in carbohydrate and glycogen metabolism in the liver tissues of streptozotocin-induced diabetic rats. The efficacy was compared with glyclazide, a standard hypoglycemic drug. Oral administration of D-pinitol to diabetic group of rats showed a marked decrease in the levels of blood glucose, glycosylated hemoglobin and an increase in plasma insulin and body weight. The activities of the hepatic enzymes such as hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glycogen synthase and hepatic glycogen content were significantly (p < 0.05) increased whereas the activities of glucose-6-phosphatase, fructose-1,6-bisphosphatase, lactate dehydrogenase and glycogen phosphorylase were significantly (p < 0.05) decreased in diabetic rats treated with D-pinitol. The results suggest that alterations in the activities of key metabolic enzymes of carbohydrate metabolism could be one of the biochemical rationale by which D-pinitol attenuates the hyperglycemic effect in diabetic rats.

D-pinitol (3-O-methyl-chiroinositol), an active principle of the traditional antidiabetic plant, Bougainvillea spectabilis, is claimed to exert insulin-like effects. This study was undertaken to evaluate the effect of D-pinitol on lipids and lipoproteins in streptozotocin (STZ)-induced diabetic Wistar rats. Rats were made type II diabetic by single intraperitoneal injection of STZ at a dose of 40 mg/kg body weight. STZ-induced diabetic rats showed significant (p < 0.05) increase in the levels of blood glucose and total cholesterol, triglycerides, free fatty acids, and phospholipids in serum, liver, kidney, heart, and brain. The levels of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol were significantly increased, and the level of high-density lipoprotein (HDL) cholesterol was significantly decreased in diabetic rats Oral administration of D-pinitol to STZ-induced diabetic rats showed significant (p < 0.05) decrease in the levels of blood glucose and total cholesterol, triglycerides, free fatty acids, and phospholipids in serum, liver, kidney, heart, and brain. The D-pinitol also lowered significantly (p < 0.05) LDL and VLDL cholesterol levels and increased significantly (p < 0.05) HDL cholesterol levels in the serum of diabetic rats. Thus, the present study clearly showed the antihyperlipidemic effect of D-pinitol in STZ-induced type II diabetic rats.

Cucurbita ficifolia is commonly used as an antihyperglycaemic agent in Asia. However, the mechanism of its action is unknown. Chemically synthesized D-chiro-inositol (D-CI), a component of an insulin mediator, has been demonstrated to have antihyperglycaemic effects in rats. In this study, we found that C. ficifolia contained fairly high levels of D-CI, thus, C. ficifolia may be a natural source of D-CI for reducing blood glucose concentrations in diabetics. We evaluated C. ficifolia fruit extract, containing D-CI, for its antihyperglycaemic effect in streptozotocin-induced diabetic rats. Oral administration of C. ficifolia fruit extract containing 10 or 20 mg D-CI kg(-1) body weight for 30 days resulted in significantly lowered levels of blood glucose, and increased levels of hepatic glycogen, total haemoglobin and plasma insulin. An oral glucose tolerance test was performed in fasted diabetic and normal rats, in which there was a significant improvement in blood glucose tolerance in the diabetic rats treated with C. ficifolia fruit extract. The effects were compared with 20 mg kg(-1) body weight chemically synthesized D-CI. Findings from this study demonstrated that C. ficifolia fruit extract was an effective source of D-CI for its hypoglycaemic effects in rats, and therefore may be useful in the treatment of diabetes.

Insulin-stimulated glucose disposal in skeletal muscle proceeds predominantly through a nonoxidative pathway with glycogen synthase as a rate-limiting enzyme, yet the mechanisms for insulin activation of glycogen synthase are not understood despite years of investigation. Isolation of putative insulin second messengers from beef liver yielded a pseudo-disaccharide consisting of pinitol (3-O-methyl-d-chiro-inositol) beta-1,4 linked to galactosamine chelated with Mn(2+) (called INS2). Here we show that chemically synthesized INS2 has biological activity that significantly enhances insulin reduction of hyperglycemia in streptozotocin diabetic rats. We used computer modeling to dock INS2 onto the known three-dimensional crystal structure of protein phosphatase 2C (PP2C). Modeling and FlexX/CScore energy minimization predicted a unique favorable site on PP2C for INS2 in a surface cleft adjacent to the catalytic center. Binding of INS2 is predicted to involve formation of multiple H-bonds, including one with residue Asp163. Wild-type PP2C activity assayed with a phosphopeptide substrate was potently stimulated in a dose-dependent manner by INS2. In contrast, the D163A mutant of PP2C was not activated by INS2. The D163A mutant and wild-type PP2C in the absence of INS2 had the same Mn(2+)-dependent phosphatase activity with p-nitrophenyl phosphate as a substrate, showing that this mutation did not disrupt the catalytic site. We propose that INS2 allosterically activates PP2C, fulfilling the role of a putative mediator mimetic of insulin signaling to promote protein dephosphorylation and metabolic responses.

Dysmorphogenesis in diabetic mothers occurs more frequently than in the general population. This phenomenon is believed to be caused by the teratogenic effects of metabolic fuel mixtures with associated membrane injury and aberrations in the biochemical constituents. The present experiment was designed to determine: 1) if hyperglycemia-induced membrane injury is associated with intracellular and/or extracellular lipid disturbances; 2) if supplemental myo-inositol therapy prevents hyperglycemia-induced embryopathy; 3) if a correlation exists between dietary myo-inositol, serum and tissue levels of myo-inositol, and conceptus development; and 4) the cellular content of arachidonic acid following myo-inositol supplementation. Sixty-five female Sprague-Dawley rats were mated, and divided into three groups. One group was nondiabetic normal controls, and two groups had diabetes experimentally induced with streptozotocin. Of the diabetic groups, one received a normal diet, while the other received a myo-inositol-supplemented diet during the period of organogenesis. Blood samples were collected on days 0 and 12 of pregnancy. Embryos and yolk sacs were analyzed for myo-inositol and arachidonic acid levels, using mass spectrochromatography. Dietary myo-inositol supplementation of diabetic mothers resulted in a significant decrease in the incidence of neural tube defects when compared with diabetics not receiving supplements (9.5 vs. 20.4%; P < 0.05). This protective effect was incomplete, based on the incidence observed in the nondiabetic controls (9.5 vs. 3.8%; P < 0.05). The myo-inositol embryonic tissue levels in the diabetic group which had been fed a regular diet without supplementation were significantly lower than in the nondiabetic group. Dietary therapy successfully restored myo-inositol levels in the yolk sacs, as suggested by similar tissue levels in diabetics receiving myo-inositol supplementation and normal controls (18.7 +/- 1.3 vs. 19.1 +/- 2.0 ng/mg; P = ns). Dietary therapy, however, failed to restore myo-inositol levels in the embryos, suggesting hyperglycemia-induced faulty transport of nutrients from the yolk sac to the embryo. No correlation was noted between maternal blood levels of myo-inositol, with or without supplementation, and the clinical outcome. Tissue arachidonic acid levels were markedly reduced in the conceptuses of diabetic mothers with (0.4 +/- 0.1 micrograms/mg) or without (0.25 +/- 0.08 micrograms/mg) myo-inositol supplementation when compared to the nondiabetic controls (3.33 +/- 0.24 micrograms/mg). These data demonstrate that diabetes-induced embryopathy is associated with a deficiency state in both myo-inositol and arachidonic acid. The myo-inositol deficiency is not demonstrated at the serum level, but rather at the tissue level, suggesting a paracrine action. Dietary supplementation of myo-inositol is associated with an increase in tissue myo-inositol levels and a decrease in malformations. This therapy holds promise for use as a dietary prophylaxis against diabetic embryopathy.

To assess effects of dietary myo-inositol supplementation on diabetes-induced vascular structural lesions, diabetes was induced in Sprague-Dawley rats with streptozotocin; one-third of these rats was fed a 2% myo-inositol diet for 9 months, one-third was left untreated for 5 months then treated with myo-inositol for the last 4 months, and one-third was untreated for the entire 9 months. Controls included untreated and myo-inositol-treated groups. Weight gain was impaired and plasma glucose, glycosylated hemoglobin, food consumption, urine volume, and albuminuria were increased significantly in diabetic versus age-matched control rats. Plasma myo-inositol levels were increased approximately fivefold in controls and approximately six- to eightfold in diabetic rats treated with myo-inositol. In general, myo-inositol did not affect any of the above parameters in control or diabetic rats. Retinal capillary basement membrane width (CBMW) was increased significantly (approximately 50% versus controls) after 9 months of diabetes. In the control group myo-inositol increased CBMW to the level of untreated diabetic rats; myo-inositol had no effect on CBMW in each diabetic group. The number of retinal capillaries containing pericyte nuclei and pericyte capillary coverage were increased in untreated as well as myo-inositol-treated diabetic rats and in the myo-inositol-treated control group. Glomerular CBMW was increased after 5 and 9 months of diabetes versus age-matched controls, and was increased even more by myo-inositol. Mesangial fractional volume of the glomerulus was increased 36% by diabetes and was decreased slightly but significantly by myo-inositol. These results indicate that diets supplemented with 2% myo-inositol (1) cause capillary basement membrane (CBM) thickening and pericyte changes in retinal capillaries of normal rats, (2) are ineffective in preventing or reversing diabetes-induced retinal CBM thickening, and (3) cause further thickening of glomerular CBM in diabetic rats.

The impaired Na(+)-K(+)-ATPase activity in peripheral nerve from diabetic rats is prevented by dietary myo-inositol (MI) supplementation in vivo and corrected by protein kinase C (PKC) agonists in vitro, suggesting that PKC may mediate the effects of nerve MI depletion on Na(+)-K(+)-ATPase activity. However, little is known about the effect of diabetes on PKC activity or peptide in rat peripheral nerve. Therefore, the effect of streptozocin-induced diabetes and dietary MI supplementation on the activity and distribution of PKC in rat sciatic nerve homogenates and cytosolic and particulate fractions was explored with histone phosphorylation assay and Western-blot analysis. PKC activity but not peptide was selectively decreased in the cytosolic fraction by streptozocin-induced diabetes, and this abnormality was partially corrected by dietary MI supplementation. These results suggest that altered MI metabolism may affect nerve PKC specific activity, and this alteration may play a role in reduced Na(+)-K(+)-ATPase activity and blunted regenerative response in diabetic nerve.

Previous studies indicate that experimental diabetic autonomic neuropathy can be largely prevented by initiating therapy at the onset of diabetes. More clinically relevant, however, is the ability of therapy to reverse established neuropathy produced by long-standing diabetes. We have examined the effect of selected therapies on established neuroaxonal dystrophy (NAD) in ileal mesenteric nerves, a rat model of diabetic autonomic neuropathy. Groups of 3-mo-old rats were made diabetic with streptozocin (STZ-D) and allowed to survive untreated for 5 mo, at which time they were begun on sorbinil, dietary myo-inositol, and daily insulin therapies or left untreated for an additional 2 or 4 mo. Ultrastructural evidence of NAD was demonstrated in ileal mesenteric nerves of rats with untreated 5-mo STZ-D and increased with the duration of diabetes. No lesions were demonstrated in control rats of any age. myo-Inositol or sorbinil administration failed to alter the severity of diabetes as measured by its metabolic indices. Institution of sorbinil or insulin treatment at 5 mo of diabetes prevented the increase in, but did not normalize, NAD at 7 or 9 mo. Dietary myo-inositol failed to significantly reverse established NAD or prevent its initial development. Morphometric examination of ileal mesenteric nerves demonstrated a decrease in the number of axons comprising each diabetic Schwann cell unit, suggestive of chronic cycles of axonal degeneration and regeneration. This parameter, clearly abnormal by 5 mo of diabetes, was not normalized by 2 or 4 mo of insulin, sorbinil, or myo-inositol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

A myo-inositol-related defect in nerve Na(+)-K(+)-ATPase in experimental diabetes has been invoked in the pathogenesis of diabetic neuropathy, but the mechanism linking altered myo-inositol metabolism and Na(+)-K(+)-ATPase regulation in diabetic nerve is uncertain. Decreased Na(+)-K(+)-ATPase in diabetic rat nerve is normalized by aldose reductase inhibitors or dietary myo-inositol, which preserve normal nerve myo-inositol content in vivo. Decreased Na(+)-K(+)-ATPase in diabetic rabbit nerve is acutely reversed by exposure to protein kinase C agonists in vitro. This study explored the relationship between the myo-inositol-sensitive and protein kinase C-agonist-sensitive Na(+)-K(+)-ATPase defects in diabetic rat nerve. Ouabain-sensitive ATPase activity was measured in an enriched membrane fraction isolated from nondiabetic, streptozocin-induced diabetic, and myo-inositol-supplemented streptozocin-induced diabetic rats before and after the membranes were exposed to protein kinase C agonists in vitro. The decreased ouabain-sensitive ATPase activity in plasma membranes from untreated diabetic rats was increased after exposure to two structurally unrelated protein kinase C agonists; the normal ouabain-sensitive ATPase in plasma membranes from myo-inositol-supplemented diabetic rats was unaffected by protein kinase C agonists. The nonadditivity and implied equivalence of the Na(+)-K(+)-ATPase defect corrected by myo-inositol in vivo and by protein kinase C agonists in vitro are consistent with the postulated existence of a deficient myo-inositol-dependent phospholipid-derived protein kinase C agonist (presumably diacylglycerol) in diabetic nerve that regulates nerve Na(+)-K(+)-ATPase either directly or via a protein kinase C mechanism.

Early functional disturbances in nerve, retina, and lens in diabetes mellitus appear to result from a common mechanism involving increased polyol-pathway activity with an associated effect on tissue myo-inositol metabolism. We tested the role of increased polyol-pathway activity in the early glomerular hemodynamic abnormalities in experimental diabetes in rats with dietary myo-inositol supplementation or the administration of sorbinil, an aldose reductase inhibitor. Each maneuver prevented the glomerular hyperfiltration of early streptozocin-induced diabetes and reversed the hyperfiltration of established diabetes of 10 days' duration. We also found that the abnormal response to captopril in diabetic rats was improved by dietary myo-inositol supplementation or sorbinil administration. Although nonhypotensive doses of captopril lowered glomerular filtration rate (GFR) in diabetic rats on a 0.01% myo-inositol diet, GFR increased substantially after captopril infusion in diabetic rats treated with sorbinil or myo-inositol supplementation. These data suggest that normalization of tissue myo-inositol metabolism restores normal responsiveness to angiotensin II; this may contribute to the reduction in GFR with the two experimental maneuvers. We also tested the interaction between polyol-pathway activation and high dietary protein intake. Aldose reductase inhibition and dietary myo-inositol supplementation had no effect on the component of increased GFR due to 50% dietary protein intake but specifically inhibited the hyperfiltration attributable to diabetes. These results suggest that hyperglycemia acts through increased polyol-pathway activity and its effects on tissue myo-inositol metabolism to play a fundamental role in the pathogenesis of the glomerular hyperfiltration characteristic of early diabetes.

Functional changes in slow-twitch soleus and fast-twitch extensor digitorum longus muscles were assessed after 2 mo of streptozocin-induced diabetes in rats. For soleus, there was a slowing of twitch times both for contraction and relaxation and a reduction of maximum tetanic relaxation rate. There was little effect on strength performance assessed by maximal tetanic tension production. Treatment with the aldose reductase inhibitor ponalrestat largely prevented relaxation defects but had little effect on contraction. For the fast muscle, twitch times were relatively unaffected, but maximum tetanic relaxation rate was reduced. In addition, tetanic tension output decreased. These changes were largely prevented by ponalrestat treatment. The effects of partial insulin therapy were also investigated. This regimen reduced hypoinsulinemia, but sufficient hyperglycemia remained to stimulate the polyol pathway. It prevented the slowing of soleus twitch contraction but had no effect on relaxation. For extensor digitorum longus, insulin produced further deleterious effects on tetanic tension and maximum relaxation rate, which were antagonized by ponalrestat. A 1% dietary myo-inositol supplement had little effect on contractile function in slow or fast muscles. It was concluded that polyol-pathway activity is an important factor underlying skeletal muscle functional changes in diabetes, probably acting through disruption of Ca2+ handling. Hypoinsulinemia was considered a secondary factor causing atrophy, particularly of fast muscles. There was no evidence of effects dependent on neuropathy.

To assess the potential of myo-inositol-supplemented diets to prevent diabetes-induced vascular functional changes, we examined the effects of diets supplemented with 0.5, 1, or 2% myo-inositol on blood flow and vascular filtration function in nondiabetic control rats and rats with streptozocin-induced diabetes (STZ-D). After 1 mo of diabetes and dietary myo-inositol supplementation, 1) 131I-labeled bovine serum albumin (BSA) permeation of vessels was assessed in multiple tissues, 2) glomerular filtration rate (GFR) was estimated as renal plasma clearance of 57Co-labeled EDTA, 3) regional blood flows were measured with 15-microns 85Sr-labeled microspheres, and 4) endogenous albumin and IgG urinary excretion rates were quantified by radial immunodiffusion assay. In STZ-D rats, 131I-BSA tissue clearance increased significantly (2- to 4-fold) in the anterior uvea, choroid-sclera, retina, sciatic nerve, aorta, new granulation tissue, diaphragm, and kidney but was unchanged in skin, forelimb muscle, and heart. myo-Inositol-supplemented diets reduced diabetes-induced increases in 131I-BSA clearance (in a dose-dependent manner) in all tissues; however, only in new granulation tissue and diaphragm did the 2% myo-inositol diet completely normalize vascular albumin permeation. Diabetes-induced increases in GFR and in urinary albumin and IgG excretion were also substantially reduced or normalized by dietary myo-inositol supplements. Increased blood flow in anterior uvea, choroid-sclera, kidney, new granulation tissue, and skeletal muscle in STZ-D rats also was substantially reduced or normalized by the 2% myo-inositol diet. myo-Inositol had minimal if any effects on the above parameters in control rats. These observations indicate that diabetes-induced increases in regional blood flow, 131I-BSA permeation, GFR, and urinary protein excretion can be markedly reduced or normalized by consumption of myo-inositol-supplemented diets that raise plasma myo-inositol levels approximately fivefold. The failure of the 2% myo-inositol diet to normalize GFR and blood flow and albumin permeation in several tissues despite markedly elevated plasma myo-inositol levels and normal or elevated tissue myo-inositol levels indicates that if vascular functional changes in these tissues are linked to altered myo-inositol levels, they are resistant to normalization by elevation of plasma myo-inositol levels. These results suggest that other factors independent of changes in relative or absolute tissue myo-inositol levels may play an important role in the pathogenesis of diabetes-induced vascular functional changes in these tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Nerve conduction impairment in experimental diabetes has been empirically but not mechanistically linked to altered nerve myo-inositol metabolism. The phospholipid-dependent membrane-bound sodium-potassium ATPase provides a potential mechanism to relate defects in diabetic peripheral nerve myo-inositol-phospholipid metabolism, impulse conduction, and energy utilization. Therefore, the effect of streptozocin-induced diabetes mellitus and dietary myo-inositol supplementation on rat sciatic nerve sodium-potassium ATPase was studied. ATPase activity was measured enzymatically in sciatic nerve homogenates from 4-wk streptozocin diabetic rats and age-matched controls either fed a standard or 1% myo-inositol supplemented diet. The sodium-potassium ATPase components were assessed by ouabain inhibition or the omission of sodium and potassium ions. Diabetes reduced the composite ATPase activity recovered in crude homogenates of sciatic nerve. The 40% reduction in the sodium-potassium ATPase was selectively prevented by 1% myo-inositol supplementation (which preserved normal nerve conduction). Thus, in diabetic peripheral nerve, abnormal myo-inositol metabolism is associated with abnormal sodium-potassium ATPase activity. The mechanism of the effect of dietary myo-inositol to correct diabetic nerve conduction may be through changes in a sodium-potassium ATPase, possibly via changes in myo-inositol-containing phospholipids.

Observations have been made on motor conduction velocity in the tibial nerve of rats given 35% myoinositol in the diet. Comparison between the values before and with up to nine weeks of dosing revealed no alteration in conduction velocity. In such animals, the free myoinositol content in the sciatic nerve was increased; there was no detectable alteration in the lipid inositol concentration. In a second series of experiments, tibial motor nerve conduction velocity in rats with streptozotocin-induced diabetes was compared with conduction velocity in diabetic animals given 1% supplementary dietary myoinositol, and with a control group of nondiabetic rats. Conduction velocity was reduced in the diabetic animals, but no influence from the added dietary myoinositol was detected. No statistically significantly difference in sciatic nerve myoinositol was demonstrated, but the sorbitol and fructose concentrations were increased. Those animals fed the myoinositol supplement had a significantly lower lipid inositol content. The significance of these findings is discussed.

This report describes a freeze fracture study of rat dorsal sympathetic chain in normal, streptozotocin diabetic on normal diet, and a group fed a 1% myoinositol normal diet. In nonmyelinated fibres, the diabetic group had significant loss of particles on the P face of juxta-axonal Schwann cell membranes, whilst myelinated nerves showed a profound loss of particles on P and E faces. In the group with adjuvant myoinositol the particle numbers were normal in both types of nerve. Axonal plasma membranes showed increased numbers of particles in the P face of the nonmyelinated membranes in the diabetic, but were normal in the myoinositol group. Myelinated axonal membranes showed no significant difference between the diabetic and the normal. Rats on a myoinositol diet showed a significant decrease in the E face particles. These results are consistent with those described in the sciatic myelinated nerves by earlier authors and reinforce the view that myoinositol is an important membrane constituent as phosphatidylinositol and is essential for the expression of normal protein particle numbers.