Insulin Resistance Abstracts 9


Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients
            (Ansar et al., 2011) Download
OBJECTIVE: To examine the effects of alpha-lipoic acid (ALA) treatment over a period of 2 months on fasting blood glucose (FBG), insulin resistance (IR), and glutathione peroxidase (GH-Px) activity in type 2 diabetes (T2DM) patients. METHODS: This study took place in Motahari Clinic, Shiraz, Iran, which is affiliated to Shiraz University of Medical Sciences from May to October 2006. Type 2 DM patients (n=57) were divided into 2 groups to receive either ALA (300 mg daily) or placebo by systematic randomization, and were followed-up for 8 weeks. After an overnight fasting and 2 hours after breakfast, patients' blood samples were drawn and tested for FBG, 2 hours PPG, serum insulin level, and GH-Px activity. RESULTS: The result of the study showed a significant decrease in FBG and PPG levels, IR-Homeostasis Model Assessment (IR-HOMA index) and GH-Px level in the ALA group. The comparison of differences between FBG and IR at the beginning and at the end of study in the ALA treated group and the placebo group were also significant. CONCLUSION: This study supports the use of ALA as an antioxidant in the care of diabetic patients.

Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.
            (Bodogai et al., 2018) Download
Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using "healthy" aged mice and macaques, we found that IR was induced by activated innate 4-1BBL+ B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium Akkermansia muciniphila impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2+ monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2+ monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR were reversible, as supplementation with either A. muciniphila or the antibiotic enrofloxacin, which increased the abundance of A. muciniphila, restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2+ monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome-monocyte-B cell axis could potentially be targeted to reverse age-associated IR.

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.
            (Brandhorst et al., 2015) Download
Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

Effects of oral zinc gluconate on glucose effectiveness and insulin sensitivity in humans.
            (Brun et al., 1995) Download
Zinc improves both insulin secretion and insulin sensitivity, and exerts insulin-like effects. We investigated its acute effects on the parameters of glucose assimilation determined with the minimal model technique from frequent sampling intravenous glucose tolerance test (FSIVGTT) in seven healthy volunteers. FSIVGTTs (0.5 g/kg of glucose, followed by 2 U insulin i.v. injection at 19 min) were performed after the subjects had taken 20 mg zinc gluconate twice (the evening before and 30 min before the beginning of the test) or placebo pills (simple blind randomized protocol). Glucose assimilation was analyzed by calculating Kg (slope of the exponential decrease in glycemia), glucose effectiveness Sg (i.e., ability of glucose itself to increase its own disposal independent of insulin response), and SI (insulin sensitivity, i.e. the effect of increases in insulinemia on glucose disposal). The two latter parameters were calculated by fitting the experimental data with the two equations of Bergman's "minimal model." Zinc increased Kg (p < 0.05) and Sg (p < 0.05), whereas SI and insulin first-phase secretion did not significantly increase. This study suggests that zinc improves glucose assimilation, as evidenced by the increase in Kg, and that this improvement results mainly from an increase in glucose effectiveness (insulin-like effect), rather than an action on insulin response or insulin sensitivity.

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents.
            (Benoit et al., 2009)  Download
Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-theta, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-theta was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-theta to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-theta nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-theta attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-theta activation, resulting in reduced insulin activity.

Fasting-Mimicking Diet Promotes Beta-Cell Regeneration to Reverse Diabetes
            (Cheng et al., 2017)  Download
Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing β cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models. PAPERCLIP.


NUTRIOSE dietary fiber supplementation improves insulin resistance and determinants of metabolic syndrome in overweight men: a double-blind, randomized, placebo-controlled study
            (Li et al., 2010) Download
The influence of dietary fiber on determinants of metabolic syndrome is controversial. The objective of this study was to determine the effects of NUTRIOSE supplementation on insulin resistance and the determinants of metabolic syndrome in overweight men. In this double-blind, randomized, placebo-controlled study, we supplemented the diets of overweight Chinese men with 250 mL of fruit juice that contained NUTRIOSE (Test group: n = 60, age = 30.4 +/- 4.3 years, body mass index (BMI) = 24.5 +/- 0.2 kg.m-2) or a maltodextrin placebo (Control group: n = 60, age = 31.6 +/- 4.1 years, BMI = 24.5 +/- 0.3 kg.m-2) at a dosage of 17 g twice daily for 12 weeks. Daily caloric intake, body composition, blood chemistry, and blood pressure were evaluated every 4 weeks during the trial. Test subjects consumed fewer calories per day and had greater reductions in body weight, BMI, body fat percentage, and waist circumference than Control subjects. All markers of glucose metabolism improved in the Test group, with increases in adiponectin and reductions in glucose, insulin, homeostasis model assessment-estimated insulin resistance, glycosylated hemoglobin, and glycated albumin (all p < 0.01). Similarly, all lipid measures improved with increases in high-density lipoprotein cholesterol and reductions in total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and triglycerides (all p < 0.01). No changes were observed in systolic blood pressure between groups. Most components of glucose metabolism and the lipid profile were significantly better in the Test than in the Control subjects. No adverse events or gastrointestinal complaints were reported in either group. Supplementation with NUTRIOSE for 12 weeks is well tolerated, lowers insulin resistance, and improves determinants of metabolic syndrome in overweight men.

Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects.
            (Manning et al., 2004) Download
OBJECTIVE:  Markers of oxidative stress and plasma alanine transferase (ALT) levels are increased and circulating antioxidant concentrations are reduced in individuals with insulin resistance. Vitamin E improves glycemic control in people with diabetes. We tested the hypothesis that vitamin E would decrease markers of oxidative stress and plasma ALT levels and improve insulin sensitivity in overweight individuals. RESEARCH DESIGN AND METHODS:  Eighty overweight individuals (BMI >27 kg/m(2)) were randomly allocated to receive either 800 IU vitamin E per day or a matching placebo for 3 months. The dose of vitamin E was increased to 1,200 IU per day for a further 3 months. RESULTS:  Plasma peroxides decreased by 27% at 3 months and by 29% at 6 months in the group that received vitamin E and were positively correlated with plasma vitamin E concentrations at the 6-month time point. At 3 months, fasting plasma glucose and insulin concentrations were significantly reduced and homeostasis model assessment increased. These changes were not apparent at 6 months. Plasma ALT concentrations declined significantly throughout the study period. CONCLUSIONS:  In conclusion, these findings indicate that vitamin E improves oxidative stress and hepatocellular function. Although insulin resistance also improves, this effect appears transient.

Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS).
            (Mayer-Davis et al., 2002) Download
OBJECTIVE:  To evaluate the association of vitamin E with incidence of type 2 diabetes and to do so separately among individuals who did and those who did not report regular use of vitamin supplementation. RESEARCH DESIGN AND METHODS:  The Insulin Resistance Atherosclerosis Study (IRAS) included 895 nondiabetic adults at baseline (including 303 with impaired glucose tolerance [IGT]), 148 of whom developed type 2 diabetes according to World Health Organization (WHO) criteria during the 5-year follow-up. At baseline, dietary vitamin E was estimated by a validated food frequency interview, usual supplement use was confirmed by supplement label, and plasma alpha-tocopherol was measured. Analyses were conducted separately for individuals who did (n = 318) and did not (n = 577) use vitamin E supplements. RESULTS:  Among supplement nonusers, reported mean intake of vitamin E (mg alpha-tocopherol equivalents [alpha-TE]) did not differ between those who remained nondiabetic (n = 490) and those who developed diabetes (n = 87) (10.5 +/- 5.5 vs. 9.5 +/- 4.8 [means +/- SD], respectively, NS). After adjustment for demographic variables, obesity, physical activity, and other nutrients, the association remained nonsignificant (odds ratio [OR] 0.80, 95% CI 0.13-5.06) for the highest level of intake (> or =20 mg alpha-TE) compared with the lowest level (1-4 alpha-TE). However, results for plasma concentration of alpha-tocopherol showed a significant protective effect both before and after adjustment for potential confounders (adjusted OR 0.12, 95% CI 0.02-0.68, for the highest quintile vs. the lowest quintile; overall test for trend, P < 0.01). Among individuals who reported habitual use of vitamin E supplements (at least once per month in the year before baseline; 259 remained nondiabetic and 59 developed diabetes), no protective effect was observed for either reported intake of vitamin E or plasma concentration of alpha-tocopherol CONCLUSIONS:  A protective effect of vitamin E may exist within the range of intake available from food. This effect may go undetected within studies of high-dose supplement use, which appears to hold no additional protective benefit.


Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial
            (Mooren et al., 2011) Download
The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects. Subjects were tested for eligibility using oral glucose tolerance test (OGTT) and subsequently randomized to receive either Mg-aspartate-hydrochloride (n = 27) or placebo (n = 25) for 6 months. As trial endpoints, several indices of insulin sensitivity, plasma glucose, serum insulin, blood pressure and lipid profile were determined. Mg supplementation resulted in a significant improvement of fasting plasma glucose and some insulin sensitivity indices (ISIs) compared to placebo. Blood pressure and lipid profile did not show significant changes. The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimization of Mg status to prevent insulin resistance and subsequently type 2 diabetes.

Vitamin A in regulation of insulin responsiveness: mini review.
            (Noy, 2016) Download
Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples 'sensing' of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases.

Measurement of insulin resistance in chronic kidney disease.
            (Pham et al., 2011) Download
PURPOSE OF REVIEW:  Insulin resistance is a known complication of end-stage renal disease that also appears to be present in earlier stages of chronic kidney disease (CKD). It is a risk factor for cardiovascular disease and an important potential therapeutic target in this population. Measurement of insulin resistance is reviewed in the context of known pathophysiologic abnormalities in CKD. RECENT FINDINGS:  Insulin resistance in CKD is due to a high prevalence of known risk factors (e.g. obesity) and to unique metabolic abnormalities. The site of insulin resistance in CKD is localized to skeletal muscle. Estimates based on fasting insulin concentration may not adequately capture insulin resistance in CKD because they largely reflect hepatic defects and because CKD impairs insulin catabolism. A variety of dynamic tests are available to directly measure insulin-mediated glucose uptake. SUMMARY:  Insulin resistance may be an important therapeutic target in CKD. Complementary methods are available to assess insulin resistance, and each method has unique advantages, disadvantages, and levels of complexity. These characteristics, and the likelihood that CKD alters the performance of some insulin resistance measurements, must be considered when designing and interpreting clinical studies.

The Effect Of Vitamin D Replacement Therapy On Insulin Resistance And Androgen Levels In Women With Polycystic Ovary Syndrome
            (Selimoglu et al., 2009) Download
Insulin resistance (IR) is one of the common features of the polycystic ovary syndrome (PCOS), and recent studies indicate the possible role of vitamin D in the pathogenesis of IR and glucose metabolism. In this study, it was aimed to determine the effect of vitamin D replacement therapy on glucose metabolism, insulin and androgen levels in obese, insulin resistant women with PCOS. Eleven women with PCOS were included into the study. The mean age of the patients were 23.6+/-5.7 years, body mass index 33.9+/-5.1 kg/m2. Six of the patients (54.5%) had acantosis nigricans and ten (90.9%) oligoamenorrhea. The mean Ferriman Gallwey score was 14.1+/-4.6. Only two women were within the normal limits of vitamin D levels as >20 ng/ml. Three weeks after the administration of the single dose of 300000 units of vitamin D3 orally, 25-hydroxyvitamin D3 significantly increased from 16.9+/-16 ng/ml to 37.1+/-14.6 ng/ml (p:0.027) and only two women were detected to have vitamin D3 levels <20 ng/ml. Although glucose and insulin levels were decreased nonsignificanltly, hemostasis model assesment-IR significantly decreased from 4.41+/-1.38 to 3.67+/-1.48 (p: 0.043). No significant alterations were witnessed at the levels of dehydroepiandrosterone sulphate, total and free testosteron, androstenedion. No correlation was found between vitamin D with HOMA and other hormonal parameters. In conclusion, women with PCOS have mostly insufficient vitamin D levels, and vitamin D replacement therapy may have a benefical effect on IR in obese women with PCOS.

Vitamin E induces regular structure and stability of human insulin, more intense than vitamin D
            (Soleymani et al., 2016) Download
Changes in human environment and lifestyle over the last century have caused a dramatic increase in the occurrence of diabetes. Research of past decades illustrated that vitamin D and E have a key role in the improvement of diabetes by reducing oxidative stress, protein glycosylation, insulin resistance and also improving beta cell function. Binding properties and conformational changes of human insulin upon interaction with vitamins D3 and E (α-tocopherol) were investigated by spectroscopy, differential scanning calorimetry (DSC) and molecular dynamic simulation. Tyrosine fluorescence quenching studies indicates changes in the human insulin conformation in the presence of vitamins. Binding constants of vitamins D3 and E for human insulin were determined to be 2.7 and 1.5 (×10-5M-1) and the corresponding average numbers of binding sites were determined to be 1.3 and 1.2, respectively. Far- and near-UV circular dichroism studies showed that vitamin E can significantly change the secondary and tertiary structures of human insulin via an increase in the content of α-helix structure. Results of DSC showed that both vitamins D3 and E stabilize the structure of human insulin. Molecular dynamic simulation results indicated that vitamin D3 decreases the helical and strand structural contents of human insulin, but vitamin E stabilizes more regular secondary structures such as helical and strand structural contents as shown by experimental results.

Activation of human insulin by vitamin E: A molecular dynamics simulation study.
            (Soleymani et al., 2019)  Download
Lack of perfect insulin signaling can lead to the insulin resistance, which is the hallmark of diabetes mellitus. Activation of insulin and its binding to the receptor for signaling process initiates via B-chain C-terminal hinge conformational change through an open structure to "wide-open" conformation. Observational studies and basic scientific evidence suggest that vitamin D and E directly and/or indirectly prevent diabetes through improving glucose secretion and tolerance, activating calcium dependent endopeptidases and thus improving insulin exocytosis, antioxidant effect and reducing insulin resistance. On the contrary, clinical trials have yielded inconsistent results about the efficacy of vitamin D supplementations for the control of glucose hemostasis. In this work, best binding modes of vitamin D3 and E on insulin obtained from AutoDock Vina were selected for Molecular Dynamic, MD, study. The binding energy obtained from Molecular Mechanics- Poisson Boltzman Surface Area, MM-PBSA method, revealed that Vitamins D3 and E have good affinity to bind to the insulin and vitamin E has higher binding energy (-46 kj/mol) by engaging more residues in binding site. Distance and angle calculation results illustrated that vitamin E changes the B-chain conformation and it causes the formation of wide-open/active form of insulin. Vitamin E increases the ValB12-TyrB26 distance to ∼15 Å and changes the hinge angle to ∼65°. Consequently, essential hydrophobic residues for binding to insulin receptor exposed to surface in the presence of vitamin E. However, our data illustrated that vitamin D3 cannot change B-chain conformation. Thus our MD simulations propose a model for insulin activation through vitamin E interaction for therapeutic approaches.



Ansar, H., et al. (2011), ‘Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients’, Saudi Med J, 32 (6), 584-88. PubMed: 21666939
Benoit, SC, et al. (2009), ‘Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents.’, J Clin Invest, 119 (9), 2577-89. PubMed: 19726875
Bodogai, M, et al. (2018), ‘Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.’, Sci Transl Med, 10 (467), PubMed: 30429354
Brandhorst, S, et al. (2015), ‘A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.’, Cell Metab, 22 (1), 86-99. PubMed: 26094889
Brun, JF, et al. (1995), ‘Effects of oral zinc gluconate on glucose effectiveness and insulin sensitivity in humans.’, Biol Trace Elem Res, 47 (1-3), 385-91. PubMed: 7779574
Cheng, CW, et al. (2017), ‘Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes.’, Cell, 168 (5), 775-788.e12. PubMed: 28235195
Li, S., et al. (2010), ‘NUTRIOSE dietary fiber supplementation improves insulin resistance and determinants of metabolic syndrome in overweight men: a double-blind, randomized, placebo-controlled study’, Appl Physiol Nutr Metab, 35 (6), 773-82. PubMed: 21164548
Manning, PJ, et al. (2004), ‘Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects.’, Diabetes Care, 27 (9), 2166-71. PubMed: 15333479
Mayer-Davis, EJ, et al. (2002), ‘Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS).’, Diabetes Care, 25 (12), 2172-77. PubMed: 12453956
Mooren, F. C., et al. (2011), ‘Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial’, Diabetes Obes Metab, 13 (3), 281-84. PubMed: 21205110
Noy, N (2016), ‘Vitamin A in regulation of insulin responsiveness: mini review.’, Proc Nutr Soc, 75 (2), 212-15. PubMed: 26729422
Pham, H, KM Utzschneider, and IH de Boer (2011), ‘Measurement of insulin resistance in chronic kidney disease.’, Curr Opin Nephrol Hypertens, 20 (6), 640-46. PubMed: 21885970
Selimoglu, H., et al. (2009), ‘The Effect Of Vitamin D Replacement Therapy On Insulin Resistance And Androgen Levels In Women With Polycystic Ovary Syndrome’, J Endocrinol Invest, PubMed: 19820295
Soleymani, H, et al. (2016), ‘Vitamin E induces regular structure and stability of human insulin, more intense than vitamin D’, Int J Biol Macromol, 93 (Pt A), 868-78. PubMed: 27642128
Soleymani, H, et al. (2019), ‘Activation of human insulin by vitamin E: A molecular dynamics simulation study.’, J Mol Graph Model, 91 194-203. PubMed: 31265936