Journal of Research in Medical and Dental Science 2018, Volume 6, Issue 5, Page No: 52-75 Copyright CC BY-NC 4.0 Available Online at: www.jrmds.in eISSN No. 2347-2367: pISSN No. 2347-2545

Nutritional Components Relevant to Type-2-Diabetes: Dietary Sources, Metabolic Functions and Glycaemic Effects

Prasad VSS1*, Dattatreya Adapa2, Dhilleswara Rao Vana3, Amarendranath Choudhury4,5, Mohammed Asadullah Jahangir6, Aparajita Chatterjee7

1Biochemistry Division, National Institute of Nutrition (ICMR-NIN), Hyderabad, Telangana, India 2Department of Microbiology, Food Science and Technology, GITAM University, Andhra Pradesh, India 3Center for Excellence in Genomics, Madurai Kamaraj University, Tamil Nadu, India 4Independent Researcher, Vizianagaram, Andhra Pradesh, India 5Alumnus, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India 6Department of Pharmaceutics, School of Pharmacy, Glocal University, Saharanpur, Uttar Pradesh, India 7UCL Institute of Neurology, University College London, London, United Kingdom

ABSTRACT Type-2-diabetes mellitus (T2DM) is a global non-communicable disease with dietary causes. This chronic disease is escalating to epidemic proportion. Medication expenditure puts additional burden on the nations already deprived of economy due to loss in terms of disability adjusted life years. Since there is no permanent cure as yet, dietary prevention and management remains the best mitigation strategy. Hyperglycemia is the characteristic symptom of T2DM. The glycaemic propensity of the food/diet is regulated at bio-accessibility, bio-availability and metabolic levels and is determined by the nutrient content and composition. Though qualitative information of certain dietary components on glycaemic regulation of the foods has been documented, studies pertaining to their effect and mechanisms have been fragmentary across several reports over the period of many years. Therefore, the present review has been conducted to interpret individual and synergistic effects of the most relevant nutritional components on the glucose propensity, insulin secretion and insulin sensitivity. This review identifies and enlists some of the most relevant nutrients to T2DM; provides various dietary sources along with their content in the context of their glycaemic indices and tracks the physiological participation of amino acid, fatty acids, cholesterol and . The pertinence of the nutritional components to different aspects of diabetic pathophysiology has been categorized. This study is of significance in formulations of diet and food supplements, meal planning as well as nutrition policy and regulation. Some of the identified nutrients may also function as metabolic biomarkers for prognosis and as potential therapeutic agents.

Key words: Glycaemic index, Nutrient, Composition, Insulin resistance, Glycosylated haemoglobin, Type 2 diabetes diabetes, Nutrient metabolism, Nutraceutical, Oxidative stress mellitus, Insulin secretion, Insulin sensitivity, Dietary fiber, , Bioactive compound, Pathophysiology of HOW TO CITE THIS ARTICLE: Prasad VSS*, Dattatreya Adapa, Dhilleswara Rao Vana, Amarendranath Choudhury, Mohammed Asadullah

Jahangir, Aparajita Chatterjee. Nutritional components relevant to type-2-diabetes: dietary sources, metabolic functions and glycaemic effects, J Res Med Dent Sci, 2018, 6 (5):52-75 Corresponding author: Prasad VSS levels [1]. Diabetes occurs when the pancreas is unable e-mail: [email protected] Received: 03/07/2018 to produce suf mounts of insulin or the cells of Accepted: 03/09/2018 the body cannot effectively utilize the insulin produced ficient a by them [2]. Dysregulation in the glucose homeostatic INTRODUCTION mechanism may lead to acute or chronic hyperglycemia [3]. This chronic condition is further characterized by Diabetes generally represents paraphernalia of alterations in protein and lipid metabolism [4] resulting metabolic disorders which are primarily characterized from defects in insulin production and/or reduced by high levels of blood sugar over a prolonged period insulin sensitivity [1]. There are primarily three types of of time. The prevalence of type 2 diabetes mellitus (T2DM) and the associated complications are on the diabetes: rise. Diabetes is a life style disease with dietary causes. Insulin is the key glucoregulatory hormone produced 1. Type 1 diabetes mellitus (T1DM) is characterized by an autoimmune destruction of the pancreatic by the pancreatic β-cells that regulates blood glucose Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 52 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75

population group [4]. It is also known as insulin tolerance and about 21.3 million women had some or dependentbeta-cells anddiabetes frequently mellitus observed or “juvenile in thediabetes” pediatric due otherAn estimated forms of 374 hyperglycaemia. million people had impaired glucose to its prevalence among children and adolescents [5]. Normal carbohydrate and insulin metabolism in 2. T2DM is characterized by a state of insulin resistance normal condition

effectively in terms of insulin secretion. This type is Dietary carbohydrates such as starch and glycogen are wherein the pancreatic β-cells cannot function acted upon by mouth salivary alpha amylase breaking the most common type of diabetes constituting 95% them down to oligosaccharides and disaccharides offrequently total diabetes observed cases in [4 the]. This adult form population of diabetes and is (Table 1). In small intestine, the pancreatic alpha amylase, sucrase, maltase and lactase breaks them into monosaccharaides (glucose, fructose, and galactose) lateralso referred in life. to as non-insulin dependent diabetes or which are absorbed through small intestinal lining into “adult-onset” diabetes since it is commonly diagnosed 1) helps them across the epithelial cells [10]. Insulin 3. Type 3 diabetes mellitus (T3DM) refers to ‘brain isthe an bloodstream. anabolic polypeptide Glucose transporter hormone which protein-1 is secreted (GLUT- diabetes’ characterized by reduction in the expression of insulin and neuronal insulin receptors pancreas adjacent to duodenum. The full chemical leading to development of insulin resistance in the structureby β-cells of in the the insulin islets ofwas Langerhans fully worked of out the in endocrine the year 1953 by Sanger [11]. Glucose that is released into the Pathophysiological changes in neuronal stress and brain of patients with Alzheimer’s disease [6,7]. blood after digestion is an important trigger for secretion of insulin. Glucose enters the beta cell by glucose overlap with Alzheimer’s disease and T2DM [8]. PI3K–GSK3β signaling as well as inflammation icial element for phosphate (ATP) thus generated inactivates potassium T3DM as vanadate was found to inhibit channeltransporter protein protein-2 leading (GLUT2) to membrane receptor. depolarization Adenosine tri Vanadium was suggested as benef phosphatase [9]. and release/secretion of insulin. Amino acids, fatty acids and ketone bodies also play a similar role in Additional secondary forms of diabetes include insulin secretion. Incretins released from the gut after gestational diabetes mellitus (GDM), characterized by consumption of food also stimulate insulin secretion. hyperglycemia during pregnancy in women without a previous history of diabetes. Certain other forms of Insulin binding to the receptor stimulates translocation diabetes manifest from prolonged use of glucocorticoids surface [12]. Glucose is then transported into the cell and undergoesof glucose metabolism. transporter In protein-4 muscle cells, (GLUT4) entry to of theglucose cell inor genesoccur regulatingas a ramification insulin ofsecretion diseases [4]. such as Cushing’s leads to glycogen and protein synthesis and inhibit syndrome, cystic fibrosis, neonatal diabetes and defects protein degradation. Insulin is directly associated with Prevalence of diabetes amino acid uptake and conversion into protein. In liver, insulin stimulates glycogen synthesis and lipogenesis illion people and inhibits gluconeogenesis. Insulin converts excess above the age of 18 years were affected with diabetes carbohydrates into glycogen in liver and muscles. withBy the total year health 2017, care it was expenditure estimated that of USD 451 850 m billion and In adipose tissue, insulin promotes lipogenesis and about 5 million deaths in the age range of 20 to 99 years inhibits lipolysis. Insulin affects mainly carbohydrate, were attributed to diabetes on worldwide basis [10]. protein and fat metabolism [13]. In adipose tissue, the About 50% of diabetic cases remained undiagnosed. carbohydrates are converted into fats by the mediation of

Table 1: Role of nutritional components in glycaemic regulation and reduction of diabetic risk Nutritional Component Food Nutrient Content Effect Reference Emmer Spelt wheat Alkylresorcinol Whole wheat grain 0.4 to 55.8 mg/100 g [14,15] Rye Inhibits activity of alpha-glucosidase enzyme

Flaxseed, walnuts, and Reduces pancreatic damage; Ameliorates insulin level; vegetableBarley oils, canola 0.2 to 11.0 g/100 g Fat [16] and soybean oils Alpha-linolenic acid Exhibits anti-oxidative Whole grain Bran layer of grains Viscosity hinders digestive enzyme access and glucose Arabinoxylan Aleurone layer absorption; Improve insulin resistance and post prandial Rye glucose response 2.37 to 30 g/100 g [17] Wheat

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Aleurone layer

Whole grains Bran layer 0.4 to 3.9 g/100 g Improves insulin sensitivity Oat Beta glucan Barley [17] Rye Wheat Whole wheat 0.16 to 294 mg/100 g Overcomes insulin resistance [14] Spelt wheat Betaine Grains Nuts Cytoprotective effects; Positive effect on pancreatic 225 to 1500 mg/day [18] Fruits cascade mechanism; Improves insulin resistance Myo-inositol Vegetables secretion of insulin by insulin-dependent signaling Common wheat Spelt wheat

Carbohydrates Chick peas [19] Baked beans (CRP) kidney beans Lowers triglycerides, HbA1c and C-reactive protein 4.5 to 74.48 g/100 g Rye Soy beverages

Chlorogenic acid Coffee 1 g/day [20] Inhibitsinsulin digestive secretion enzymes; and activates Blocks insulin sodium receptors dependent Cereals glucose transporter SGLT1 in small intestine; stimulates

Chromium 50 to 200 µg/day [21] Vegetables Legumes Binds with low molecular weight oligopeptides and Fruits influences insulin metabolism; Lowers blood glucose and HbA1c and improves insulin sensitivity Regulates glycosylated haemoglobin; Participates in Soybean Brown rice Flaxseeds 3.8 to 25.5 g/100 g acids; reduces starch susceptibility to digestive enzymes; [22] colonicSCFA modulate fermentation gluconeogenesis and generation and lipogenesis;of short-chain lowers fatty Dietary fibre Whole grains Legumes Whole grains HbA1c Fats 0.38 to 35 g/100 g [19] Soy bean Legumes Increases LDL Cholesterol, triglycerides and HbA1c Cereals Modulates glucose from blood to muscle; promotes 25 to 3300 mg/100 g insulin secretion; blocks sodium dependent glucose [20] Nuts Legumes Whole grains Phenolic Acids transporter SGLT1 in small intestine [14,23,24]

0.11 to 117.1 mg/100 g Inhibition of α-amylase and α-glucosidase activities Legumes Phytic Acid Whole grains 0.9 to 15.2 g/100 g Bran layer α-glucosidase and α-amylase inhibition [17] Polyphenol Legumes 0.15 g/100 g [25,26] Whole wheat carbohydrate source; improves insulin resistance Brown algae Anti-oxidative mechanism; inhibits glucose release from Cereals Vegetable protein poses lesser risk of T2D than animal Protein protein Prunella vulgaris 2.08 to 17.47 g/100 g [27] Triterpenic Acid Legumes 0.34 to 8.5 mg/100 g [28] Centella asiatica Increase insulin sensitivity; anti-obesity; decrease glucose production; anti-oxidant; enzymatic regulation such as increase in lipolysis leading to generation of fatty acids; increase in small dense low density lipoproteins signalinsulin. cascade Myo-inositol, and increases a carbocyclic insulin sugar sensitivity found (Table in grains 1). and nuts also benefits in T2DM, aid in insulin dependent blue berry with corresponding GI of 59. gluconeogenesis(LDL), increased leveland ofdecrease hepatic triglycerides;in protein synthesisdecrease Almost upto 400 mg/100 g of myo-inositol was noted in in high density lipoproteins (HDL); higher rate of Insulin metabolism in diabetic condition and release of free fatty acids due to activation of lipase. These[29,30]. fatty Insulin acids deficiency are then leadsused toas lipolysissource of of energy. the fat In chronic diabetic condition, due to hindered insulin secretion, effects contrary to normal health materialize ketosis and acidosis [31]. Excess intake of fat during insulin deficiency leads to Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 54 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75

Pathophysiology of diabetes the development of pathophysiological conditions [31]. The schematic representation of T2DM pathophysiology The increasing interest in research in diabetes has led is presented in Figure 1. The post prandial glucose to a better understanding of the pathophysiology of hyperglycaemic interventions. The combined effects of andmolecules Krebs enter cycle into in the mitochondria, pancreatic β-cell generating by means ATP of geneticthe disease constitution, and thereby lifestyle development changes and of aging several increase anti- molecules.GLUT2. The With intracellular the increase glucose in entersATP: ADP into ratio, glycolysis the the overall risk of diabetes. These factors contribute to hyperglycaemia through mechanisms of impaired insulin altered potential due to higher level of positively charged secretion and impaired insulin action in target cells potassium ions, channel the getsmembrane blocked. gets Consequently, depolarized. withThis (insulin resistance) which jointly contribute towards activates voltage dependent calcium channel causing

Figure 1: Diagrammatic representation of pathophysiology in type 2 diabetes mellitus (T2DM) (a) Glucose transporter type 2 (GLUT2) membrane transporters facilitates entry of post prandial blood glucose into the cell. Intracellular glucose is phosphorylated by glucose-6- phosphatase to glucose-6-phosphate that enters glycolysis cycle generating pyruvate and adenosine triphosphate (ATP). Pyruvate enters tricarboxylic acid (TCA)cycle further generating ATP. Increase in ATP: ADP ratio blocks KATP channel leading to membrane depolarization thus letting Ca2+ ions into the cell through voltage dependent/gated calcium channel. Ca2+ ions stimulate the secretion of insulin peptide; (b) In healthy individuals, insulin binds to insulin receptor which initiates phosphorylation based signaling cascade that results in translocation of intracellular GLUT4 to membrane for uptake of glucose molecules; (c) In diabetic condition, insulin receptors become non-functional and cytoplasmic GLUT4 does not get translocated to membrane resulting in insulin resistance. Consequently, glucose uptake does not take place which leads to hyperglycemia (increased blood sugar levels).

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complications was observed from cross sectional, of transcriptional activators such as hepatocyte nuclear prospective and interventional studies [44]. The glycated influx of calcium ions. The calcium ions cause expression initiates insulin synthesis and secretion. which measures the percentage of blood sugar attached factor 1 alpha (HNF1A) and 4 alpha (HNF4A) which tohaemoglobin hemoglobin. (HbA1c) Conventional is a marker therapy for chronic for periodontal glycaemia clinical onset of the disease) leads to impaired insulin According to the American Diabetes Association (ADA), secretionImpaired β-cellwhich functionis clinically (generally observed observed as a decline prior toin thetreatment diagnosis even of diabetes led to 0.4% is usually reduction based in on HbA1c the glucose [45]. the glucose responsiveness of the cells in the pancreas [32]. Impaired glucose tolerance (IGT), characterized g oral glucose tolerance test (OGTT) are the most widely criteria, wherein fasting plasma glucose (FPG) or the 75 post meals causes hyperglycaemia. Associated risk factorsby decrease such as in glucose glucose-responsive toxicity and lipotoxicity insulin secretion further diagnosticaccepted diagnostic test which tests. indicates A FBS the value average ≥ 126 blood mg/dl sugar is enhance the progression of impaired insulin secretion. considered diabetic [46]. The HbA1c test is a widely used If this condition remain untreated, it would result levels over the past 60 to 90 days. The ADA affirmed that Thean individual risk and incidencewith a HbA1c of diabetes percentage is measured of ≥ 6.5 is indiabetic terms in overworking of the pancreatic β-cells, leading to and a percentage of 5.7-6.4 indicates pre-diabetes [42]. number)progression [33]. of The apoptosis progressive and finally decline a declineof pancreatic in the composition plays prominent role in the management pancreatic β-cell mass (the product of β-cell size and of glycaemicdisease symptoms.index (GI), HbA1cThere orare insulin several resistance. nutritional Diet elevation in the blood glucose level (hyperglycaemia) components in the diet that has relevance to the risk of marksβ-cell functionthe development and mass of overT2DM time [34,35]. accompanied with diabetes either directly or indirectly.

Insulin resistance occurs when the cells of the body There are several reports that indicate the GI and glycaemic fail to respond to physiological levels of insulin that is produced, causing an increase in the level of role and effect of nutritional components on glycaemic blood glucose [36]. In peripheral cells, under healthy potentialload (GL) were of foods. fragmentary However, and reports scarce. pertaining Structuring to and the condition, the insulin peptide binds to the insulin engineering of food components within the food matrix receptor triggering phosphorylation based signal with a control on its digestion and their bioavailability has glucosecascade into which cells translocates and inhibits GLUT4 the usage from of cytoplasm reserve fats to been proposed for meeting the nutritional requirements membrane (Figure 1). GLUT4 then facilitates uptake of of vulnerable population groups [47]. Therefore, the insulin receptors in the cells of peripheral tissues componentscurrent review on the was modulation undertaken of glycaemic to qualitatively propensity. and for energy [32]. However, under diabetic condition, Thequantitatively metabolic events estimate associated the effect with of modulation the nutritional of GI Therefore, the cells cannot absorb glucose contributing for each component has also been indicated that have become inactive and GLUT4 remains in the cytoplasm. clinical relevance. T2DM is essentially a result of combination of inhibition to the development of chronic hyperglycemia [37]. Role of nutritional components in blood glucose by genetic determinants, [38] level of physical regulation activity,of insulin dietary secretion pattern, and insulin aging resistance and lifestyle as influenced [39,40]. Excessive intake of carbohydrates, oils and fat leads to Nutrition plays a key role in prevention of diseases and hyperglycemia and hyperlipidemia causing nutrient is essential to maintain a healthy lifestyle and accurate overload and imbalance. Prolonged exposure to such functioning of the body metabolism. Intake rates of over nutrition leads to lipid peroxidation and glycation. nutrients were linked to body weight as well. Altered fat, These developments result in insulin resistance. These consumption correlates to lower body weight. Different are crucial contributors to the development of T2DM nutritionalcarbohydrate components and cereal that fiber are intake found with to be low associated GI food [40,41].factors, along with consumption of energy-rich foods with glycaemic metabolism along with the range of their concentrations in diverse food sources and their Diagnostic parameters of diabetes effects on insulin secretion, insulin sensitivity and blood glucose level are summarized in Table 1. T2DM patients Prominent symptoms of diabetes include polyuria, tend to consume foods containing nutrients in a pattern polydipsia, weight loss, and blurred vision. Certain long term complications result in retinopathy, peripheral neuropathy, nephropathy, foot ulcers and kidney failure T2DMthat is quitepatients different consume to the relatively normal highersubjects. amounts Based onof [42]. Diabetes is a major risk factor for periodontitis, totala cross fat, sectional monounsaturated study, Breen fat etand al. polyunsaturatedhave observed that fat a chronic disease affecting periodontal ligament and alveolar bone [43]. A direct and proportional relation between severity of periodontitis and diabetic diabeticand protein subjects but the[48]. intake of carbohydrates, non-milk sugars and dietary fiber were relatively lesser than non-

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In T2DM, dietary causes are considered more reliable Mucuna seeds 5.28 g/16 gN [93] and prominent risk factors when compared to genetic, [80,94] epigenetic or environmental factors [49]. Although protein - 7.693.09 g/100to 3.25 g clinical factors such as conditions of overweight and BrownMilk rice 68 ± 4 [94] g/100 g protein obesity are risk factors, it can be observed that diabetes L-Arginine 5.58 to 8.83 manifests even in individuals with normal body mass 15-60 [94] g/100 g protein Mucuna seeds [93] linked to nutrient metabolism is very relevant to T2DM. Legumes 12-70 8.40 g/100 g index (BMI). It is quite evident that the energy metabolism [94] The energy imbalance that predisposes an individual 7.88protein g/16 gN - for diabetes is either regulated by physical activity or 9.83 to 10.66 BrownMilk rice 68 ± 4 [94] diet composition of the food. In case of lack of physical g/100 g protein utilization of excess glucose, diet regulation comes Leucine 15-60 [94] to the prominence in management of diabetes. An g/100 g protein 6.73 to 8.91 imbalance between the actual demand of energy within MucunaLegumes seeds 4.16 g/16gN 12-70 [93] 4.08 g/100 g the cells and the extent of nutrient availability is the - [94] fundamental and pivotal in the development of T2DM protein Isoleucine 5.30 to 6.20 [50]. Consumption of a diabetic diet, including complex BrownMilk rice 68 ± 4 [94] g/100 g protein carbohydrates, vegetables, lentils and generally, foods 3.38 to 4.34 15-60 [94] g/100 g protein MucunaLegumes seeds 4.23 g/16 gN 12-70 [93] inwith T2DM. a low Therefore, GI and GL there cause is apossibility modest rise of reductionin blood sugar in its [94] prevalencewhich is essential by dietary in preventing management. long-term For effective complications dietary protein Valine 6.725.86 g/100to 6.40 g policy, it is important to have updated information BrownMilk rice 68 ± 4 [94] on the role of different dietary components on blood g/100 g protein 4.09 to 5.53 glucose levels. Different nutritional components that 15-60 [94] g/100 g protein have relevance to the metabolic glycaemic effects have 0.2 g/100 g LegumesWheat 12-70 [94] been enlisted in Table 2 along with their dietary food bran 0.3 g/100 g 74 ± 2 [94] Table 2: Quantitative information of T2DM related nutrients, their bran food sources and corresponding glycaemic indices Pumpkin seed Barley <1% 28 ± 2 [95] Nutrient Food Content GI Reference oil Acid Whole Cooked dry Alpha-linolenic - [96] Insoluble legume fatty acids Watermelon 25.370.3 tog/100 0.6 g 77.2 [78] 2.544% to 41.7%of fatty of sorghum flour Canola oil 12-70 Sapota 9.1 to 10.9 acids dietary fiber 76 ± 4 [79,80] Whole 16.10 mg/100 g [97][94] - [79] Soluble dietary Triterpenic Cooked dry 0.34 to 8.5 Brown rice 68 ± 4 [96] 0.970.3 g/100 g/100 g g 77<55 ± 8 [78-81][82,83] acid legume mg/100 g sorghum flour 2.4 g/100 g [80,82] Oleanolic acid Apples 0.28 g/100 g 12-70 [94] fiber Coconut flour 100 to 400 0.18 to 3.10 59 [84] Oleanolic acid Olive 36 ± 2 [98] Wheat flour mg/100 g 74 ± 2 g/100 g BlueCow berrymilk 4 mg/100 g [84] Aloe vera 0.10 g/100 g - [98] Myo-inositol Pea 5 to 20 µmol/g 22 [85] 140 mmol [82] 31 ± 2 AcetateLupeol - 355 mmol [94] Wheat [80,86] Coconut flour - g/100 g [82] 2.37 to 10.75 Propionate Wheat flour 74 ± 2 4 to 8 g/100 g 74 ± 2 86 mmol [94] Coconut flour 47 mmol - Rye 8.60% 29 [88] [82] Barley 28 ± 2 [87] Wheat flour 74 ± 2 [89] 225 mmol [94] Coconut flour 173 mmol Arabinoxylan Whole rye 8.60% 29 [88] Butyrate 1.38 mcg/100 g [94] Wheat flour 1.35 to 2.75 % 74 ± 2 Wheat flour 74 ± 2 [80,90] 2.38 mcg/100 g [94] Brown rice 68 ± 4 Rice 2 to 3% [83,90] 1.35 to 1.69 Wheat flour 5.53 to 7.19% 74 ± 2 Barley 28 ± 2 [94] 3.98 to 5.44% [90,80] Biotin mcvg/100 g 73 ± 4 Maize 1 to 2% 59 [83,90] Banana 0.02 mg/100 g 51 ± 3 [94] Barley 28 ± 2 Pumpkin seed Rye 29 [83,90] [95] Barleyoil mcg/g 28 ± 2 Wheat 0.48 g/100 g [91] Vitamin E 6.9 to 7.6% Cooked dry 27.1 to 75.1 4.16 g/100 g [91] - [96] 74 ± 2 legume mg/100 g Oat 4.40% 50 [92] 0.26 to 1.78 Barley 28 ± 2 0.69 mg/100 g 12-70 [94] Whole Beta glucan 0.12 g Brown rice 68 ± 4 77 ± 8 [78,81] sorghum flour

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1.22 to 1.63 Milk [94] mcg/100 g carbohydrate content in the food/diet, GI provides Vitamin D Orange 0.34 mcg/100 g 39 ± 3 [94] comprehensiveUnlike GL, which representation is solely of concerned the entire withfood/diet the composition [51]. Fat, starch and alcohol intake was Chickpea 43 ± 3 [94] mcg/100 g positively associated with average GI. Intakes of mono 1.75 to 1.93 Wheat 28 ± 9 [94] 2.5 mg/100 g [94] Iron 3.27 mg/100 g 74 ± 2 with GI. Radovanovic et al. have observed that when 1.02 mg/100 g [94] Barley 28 ± 2 Jerusalemand disaccharides artichoke and was fibers used were as functional inversely food associated source Pineapple pulp 2.53 mg/100 g 65 [94,99] Brown rice 68 ± 4 in developing extruded food, it has lowered the GI [52]. Wheat 109 mg/100 g [94] Such property was attributed to contribution in terms Magnesium [94] 74 ± 2 93.91 mg/100 g [94] Barley 79 mg/100 g 28 ± 2 carbohydrate and lipids. Murakami et al. observed that Wheat 36 mg/100 g [94] Brown rice 68 ± 4 dietaryof high totalGI was dietary positively fiber correlated content, and with lower starch protein, and 29 mg/100 g [94] Calcium 74 ± 2 10.93 mg/100 g [94] Barley 28 ± 2 Pineapple pulp 10.41 mg/100 g 65 [94,99] Brown rice 68 ± 4 GL and negatively associated with saturated fatty acids 0.005 mg/100 g [94] of(SFA), GI withtotal sugars,total carbohydrates dietary fiber and[53]. total There fat was(in men) also Chromium Soybean [94] among British adults and there was no correlation Brown rice mg/100 g 68 ± 4 0.003 to 0.007 Pineapple 0.008 mg/100 g 16 ± 1 [94] no association between GI and BMI in both men and Cooked dry 11.8 to 25.9 mg [96] women. Burger et al. have reported that intake of high legume GAE/100 g 59 ± 8 whereas higher intake of carbohydrates and sugars was dietary fiber was inversely associated with mortality risk Whole 12-70 positively associated with mortality risk among diabetic Polyphenol 833 individuals with normal weight [54]. Goletzke et al. 49 77.2 [79][82] have observed that among pregnant women, dietary sorghum flour 2.81 mg/100 g [94] GI was inversely associated with micronutrient intake Coconut flour - 0.06 mg/100 g [94] Brown rice 68 ± 4 1.44 to 2.15 Chlorogenic Apple [94] Brown rice mg/100 g 68 ± 4 acid [55]. Higher GI was negatively correlated to intake of 0.51 to 0.58 Water melon 36 ± 2 [94] calcium, dietary fiber, riboflavin, folate, potassium, mg/100 g observed that consumption of vegan diet or conventional diabetesand magnesium diet for 22 intakes. weeks Turner-McGrievy in 99 participants et increased al. have 0.02 mg/100 g 76 ± 4 [94]

Ferulic acid Apple [94] Brown rice mg/100 g 66 ± 5 0.31 to 0.79 Orange 0.19 mg/100 g 36 ± 2 [94] carbohydrate, fiber and several micronutrients and improved alternate health eating index (AHEI) which Wheat [94] monounsaturated fatty acids (MUFA), and g/100 g 43 ± 3 was negatively correlated to HbA1c [56]. Intake of 0.03-0.15 74 ± 2 [94] 489 to 1429 Wheat [94] fiber leads to improved endothelial vascular activity, Barley 42-51mcg/g mcg/g 28 ± 2 mechanisms. These improvements cause glucose control lipid profile, anti-oxidativeIndividual fatty and acids anti-inflammatory such as linoleic Rye 7429 ± 2 [100] Alkylresorcinol mcg/g 720 to 761 in terms of HbA1c. wheat [100] effect on pancreas by virtue of their antioxidant activity mcg/g and alpha-linolenic acid were found to have protective 439 to 647 (Table 1) [16]. 42 to 51 mcg/g 74 ± 2 [100] Wheat 412 mcg/g [101] Barley 28 ± 2 Recently, functional and novel food sources such Rye 110 mg/100 g 29 [100] 74 ± 2 Wheat 80 mg/100 g [100] [94] 74 ± 2 isas due spelt to wheatoccurrence have of been substantial identified amounts as appropriate of blood 386 mg/100 g [94] Phytic acid Brown rice 742 mg/100 g 66 ± 5 glucosedietary sourcelowering compared and multiple to common bioactive wheat components [57]. This Kidney bean [94] Barley mg/100 g 28 ± 2 White rice 465-481 [102] antioxidants (Table 1). These components are known 24 ± 4 such as dietary fiber, phytic acid, alkylresorcinols and Potato [102] to regulate blood glucose level and optimize insulin 1.3 HU/mg 72 ± 9 [102] sensitivity. Though the macronutrients play an important 5.5 HU/mg 70 ± 8 Soybeans [102] role in glycaemic response, the micronutrients and Lectin Banana 13 HU/mg 62 ± 9 Chick pea [102] the bioactive components act either individually or in 87 HU/mg 15 ± 5 a synergistic manner. The higher protein content and 180 HU/mg 36 ± 5 fat content particularly that of unsaturated fat in spelt sources and corresponding GI value wheat favored glycaemic control. be noted that the GI value of food is determined by the complete nutritional composition ands. However,energy content it has toof When an imbalance occurs in the food intake and energy the food or diet. expenditure, the condition leads to excess nutrient

Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 58 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75 availability in the human body. Fats are stored as body fat mass leading to adiposity. The changes send nutrient related signals to brain. Nutritional changes also lead to study,animal Malik protein et withal. have plant reported protein that has totalbeneficial protein effects and animalon the protein glycaemic intake control raised [27,65]. the risk In of an T2DM independent b nephropathy or even cardiac disease or atherosclerosis. Impairedimpaired insulinglucose secreting and lipid beta-cell metabolism functioning, leads diabeticto fatty y 7% possibleand 13%, mechanism respectively could[27]. However,be the presence intake of vegetableof higher concentrations of the nutrients such as glucose, lipids protein caused moderate decrease in such risk [27]. A liver,and amino neurodegeneration acids lead to andvascular inflammation. complications Elevated and proteins [65]. In vitro studies and randomized controlled amounts of L-arginine in plant proteins than animal leads to decrease in the cellular uptake of glucose, injury to the insulin sensitive tissues. Insulin deficiency increased protein catabolism, and increased lipolysis. trials suggest that L-arginine promotes insulin secretion from β-cells and improves insulin sensitivity in T2DM electrolyte depletion. Increase in the amino acid content acid which causes membrane depolarization. This allows [66-68]. L-Arginine is a cationically charged polar amino inHyperglycaemia blood plasma causesleads to glucosuria, loss of nitrogen osmotic through diuresis urine. and Increase in free fatty acids in plasma leads to ketogenesis, ketouria and ketonemia. All these abnormalities due to foundcalcium to ion be denseinflux intoin brown the β-cells rice, macuna which mediates seeds, milk insulin and altered nutrient metabolism lead to dehydration and legumesexocytosis (Table (Figure 2). 2). Contrastingly, The distribution based of on L-arginine randomized was acidosis which is a major concern. Nutrition therapy is parallel group study, Sucher et al. have reported that effective in reducing the impact of higher blood glucose animal and plant protein have similar improvement in level. Dworatzek et al. reported that nutrition therapy has metabolism and cardiovascular risk factors in T2DM the potential to improve clinical outcomes by reducing people and difference in amino acid composition does not affect metabolic responses [69]. This reveals that the high GI carbohydrate foods with low GI foods can be glycemic modulation depends more on the amino acid helpfulHbA1c byin 1%management to 2% and of have T2DM emphasized [23]. In addition that replacing to the macronutrient composition of the food particularly that composition rather than the source of protein. of protein and carbohydrates, the food physical state also has substantial effect on the post prandial blood glucose level. Shafaeizadeh et al. have reported that glutamine as well as branched chain amino acid such as leucineDietary participate amino acids in suchATP producing as alanine, tricarboxylic L-arginine acid and glucose response that were comparable whereas solid cycle (TCA cycle) at different stages. formulationsliquid foods differing with similar in carbohydrate protein and quality, energy produced density elicited different GI and insulin responses [58]. Pyruvate is generated from alanine (by transamination) and glucose (by glycolysis). Acetyl CoA is generated from pyruvate (by oxidation) and leucine (transamination overloading does not cause any change in the and dehydrogenation). Glutamine gets converted to mitochondrialHowever, it wasoxidative previously capacity noted[59]. The that changes nutrient in the nutrient availability during fasting and feeding are cycle generates electrons that participate in electron chainα-ketoglutarate. transport Thechain reducing resulting equivalents in phosphorylation from TCA release of insulin accordingly [60]. Insulin sensitivity of ADP to ATP by ATP synthase. When ATP: ADP ratio sensed by β-cells of the pancreas which engage in the in different tissues is related with redox balance increase, ATP sensitive potassium channel (KATP) and mitochondrial function. The nutrients modulate open, causing membrane depolarizat different metabolic pathways that exert control on voltage gated calcium channel (VGCC) gets activated tions have been allowing Ca2+ into the cell promoting calciumion. Consequently, dependent detailed by Adapa et al. [62] for treatment of diabetes. Precisioninsulin functioning nutrition [61].has beenHerbal suggested formula for prevention and management of diabetes [63]. exocytosis of insulin [70]. degrade incretin peptide hormones that regulates blood Role of protein and amino acids glucoseDipeptidyl level. aminopeptidase Such activity is IV demonstrated (DPP-IV) such in as biological gliptins, Consumption of legu of lentils was found to be inversely associated with inhibitory peptide motif thus effecting antidiabetic models [71]. Food hydrolysates may contain DPP-IV incidence of T2DM in mesadults and [64]. more It is well specifically known that legumes are rich source of proteins. It was found that well as aromatic amino acids such as isoleucine, leucine, activity [72]. Branched chain amino acids (BCAA) as protein intake does not alter the glycaemic indicators. In valine, tyrosine, and phenyl alanine can be used as T2DM individuals, intake of protein leads to better insulin nutrient biomarkers for prediction of diabetic condition response. Several studies have shown that replacing

[73]. BCAA were associated with insulin resistance [74]. Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 59 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75

Figure 2: Metabolic pathway representing positive effects of arginine, alanine, leucine and glutamine in insulin secretion within pancreatic β-cell. (A) Alanine is converted to pyruvate which is then catalyzed by pyruvate dehydrogenase/pyruvate carboxylase to form Acetyl CoA or oxaloacetate. Leucine is catalyzed by amino transferase (AT) generating α-ketoisocaproate which is then catalyzed by branched chain ketoacid dehydrogenase (BCKDH) to form Acetyl CoA. Similarly, glutamine is converted to glutamate which is then catalyzed by glutamate dehydrogenase to form α-ketoglutarate. Acetyl CoA, oxaloacetate and α-ketoglutarate participate in TCA cycle generating ATP. The ATP produced via TCA cycle leads to membrane depolarization that facilitates Ca2+ influx which further helps in insulin secretion. L-Arginine causes membrane depolarization that allows calcium ion influx into the β-cells which mediates insulin exocytosis. (B) Branched chain amino acid (BCAA) mediated inhibition of insulin response in peripheral tissues. Insulin binding to insulin receptor (containing tyrosine protein kinase) causes autophosphorylation which leads to activation of insulin receptor kinase. The insulin receptor binds to insulin receptor substrate 1 (IRS1) and phosphorylates it. Phosphorylated IRS1 binds to phosphoinositide-3-kinase (PI3K)which further phosphorylates phosphatidylinositol diphosphate (PIP2) to form phosphatidylinositol triphosphate (PIP3). PIP3 activates PIP3 dependent kinase which results in phosphorylation of protein kinase B (PKB/Akt). Akt inhibits tuberous sclerosis complex (TSC). This leads to activation of Ras homolog enriched in brain (Rheb). Rheb in turn activates mammalian target of rapamycin complex 1 (mTORC1). Activated mTORC1 further activates Ribosomal protein S6 kinase beta-1 (S6K1) which destabilizes IRS1 causing reduced insulin signaling. BCAA causes insulin resistance by directly activating mTORC1 through Heterodimeric RagGTPases.

In a randomized single blind cross over study comprising branched chain amino acids and aromatic amino acids of 11 diabetic subjects, intake of whey proteins prior to such as phenyl alanine and tyrosine do have association meals was found to improve post prandial glycaemia and acids that are glucogenic such as alanine, glutamine, or with insulin resistance [76]. Leucine, isoleucine and glycine,stimulate , insulin secretion arginine, [75]. and There are certain which amino are mammalianvaline have target branched of rapamycin aliphatic sidecomplex chain. 1 (mTORC1) BCAA are not associated with insulin resistance; however, dietary byuseful converting in improving Rag to their body active composition. nucleotide BCAA bound activates form.

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Then, heterodimeric RagGTPases relocates mTORC1 to enriched in brain (Rheb). Activated mTORC1 in turn homeobox 1 (PDX-1) in the cytosol and reduces its peri-nuclear region containing its activator Ras homolog nuclear localization thus reducing the GLUT2 expression. Consequently, failure to respond to extracellular glucose which phosphorylates and destabilizes Insulin receptor as well as inhibition of ER-Golgi protein trafficking activates Ribosomal protein S6 kinase beta-1 (S6K1) also cause proteolysis of carboxypeptidase E protein (CPE)by SFA that leads is toinvolved proinsulin in the buid-up biosynthesis in beta of cells. peptide SFA hormones. These effects of SFA result in diminution substrate 1 (IRS1) [77]. Thus, active mTORC1 inhibits of glucose stimulated insulin secretion. MUFA are insulin signaling for glucose uptake. However, the risk of T2DM due to BCAA intake depends on the dietary considered beneficial for glucose control in T2DM [103]. Rolepattern of fats,[77]. fatty acids and cholesterol apoptosis. MUFA also has antagonistic effect on the damageMUFA block induced the enzymeby saturated caspase-3 fatty acids that induces(SFA). Inclusion cellular The fatty acid metabolism in relation with diabetic condition has been depicted in Figure 3. Free fatty acids of omega-3 fatty acids in the diet in diabetic people (FFA) in the plasma enter into the cells of the peripheral complications and maintaining renal function [104]. was found to be beneficial in preventing cardiovascular protein coupled receptor 120 (GPR120) which leads to On the other hand, Omega-3-fatty acid binds with G formstissues. lipids These which fatty acidsafter arelipolysis converted form into diacylglycerol long-chain (DAG)fatty acid and acyl-CoA ceramide. (LCFA Under CoA). hyperlipidemic Oxidation of condition,LCFA CoA the excess of these metabolic derivatives hinder the anti-inflammatory response by repressing macrophage insulin response signal cascade as depicted in Figure 3, 4)induced and enhancement tissue inflammation in the insulin that includessensitivity inhibition [105,106]. of causing insulin resistance. GPR120Interleukin-1 is a betareceptor (IL-1β) of andlong Toll-like chain unsaturated receptor-4 (TLR- fatty acids and is abundantly expressed in adipose tissue, is more important than the macrophages and intestine. Its function is considered as pivotal in management of diabetes as it enhances isThe no qualitymention of of the the fatamount of fat restriction among the overall insulin sensitivity. In adipocytes, binding of diabeticquantity subjects. of the fat Saturated among diabetic fatty acid populations. (SFA) such There as protein. Upon receiving the insulin, the insulin receptor unsaturated fatty acid with GPR120 activates Gq/11 palmitic acid sequester the pancreatic and duodenal

Figure 3: Sequential events in free fatty acid (FFA) mediated insulin resistance in skeletal muscle cell. Excess of FFA in plasma enters the muscle cell and gets converted into long-chain fatty acid acyl-CoA (LCFA CoA). LCFA CoA gets oxidized to form lipids which undergo lipolysis generating diacylglycerol (DAG) and ceramide. DAG and ceramide activates protein kinase C (PKC) which inturn activates kappaB kinase (IKK) and c-JUN NH2-terminal kinase (JNK). PKC, IKK and JNK stimulate serin-threonine phosphorylation which blocks tyrosine phosphorylation and dissociates phosphoinositide-3-kinase (PI3K) from insulin receptor substrate (IRS1) while ceramide directly decreases Akt/protein kinase B (PKB) phosphorylation. Down-regulation of insulin signal cascade (from IRS1 to Akt)prevents GLUT4 translocation to membrane and hence glucose uptake is affected rendering the cell insulin resistant.

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Figure 4: Graphical illustration representing sequence of events in amelioration of insulin resistance by polyunsaturated fatty acid (PUFA) under diabetic condition. Docosahexaenoic acid (DHA; 22:6n-3), an Omega-3-fatty acid in the plasma, is received by guanine nucleotide- binding regulatory (G) protein-coupled receptors, also called as the G protein-coupled receptor 120 (GPR120) or free fatty acid receptor 4 (FFAR4) in adipocytes. GPR120 functions as signaling molecule which activates heterodimeric G proteins (Gq/11). Gq/11 is then tyrosine phosphorylated by insulin receptor (IR) subsequently forming complex with p110α-subunit of phosphoinositide 3-kinase (PI3K). The activated PI3K is followed by signaling cascade involving phosphatidylinositol 4,5-bisphosphate (PIP2), phosphoinositide-3-kinase (PIP3), pyruvate dehydrogenase kinase 1 (PDK1) and protein kinase B (PKB) resulting in translocation of glucose transporter type 4 (GLUT4) to plasma membrane for glucose uptake, thus increasing insulin sensitivity. In macrophage cells, the toll-like receptors-4 (TLR4), functions as a signaling receptor for lipopolysaccharide (LPS) whereas, tumor necrosis factor receptor (TNFR) is a receptor for cell signaling cytokine, the tumor necrosis factor (TNF). TLR4 and TNFR initiate pro-inflammatory cascade by phosphorylating transforming growth factor β (TGF-β)-activated kinase 1 (TAK1). The binding of omega -3-fatty acid (ω-3 FA) with the receptor (GPR120) leads to subsequent association of the receptor with β-arrestin2. This is followed by internalization of both receptor and β-arrestin2 and their co-localization in the cytoplasmic compartment. This allows association of β-arrestin2 with (TGF-beta activated kinase 1 (MAP3K7) binding protein 1) which delinks TAB1 from TAK1. Due to this delinking, phosphorylation of TAK1 gets inhibited. Inhibition of TAK1 results in the blocking of inflammatory pathways such as inhibitor of nuclear factor kappa-B kinase subunit beta/ nuclear factor kappa-light-chain-enhancer of activated B cells (IKKβ/NFκB) and c-Jun N-terminal kinase/ Activator protein 1 (JNK/AP1) pathways ultimately leading to reduced insulin resistance.

gastric emptying and sends signals of satiety to brain. and extra pancreatic cells. In intestine, GLP-1 delays associates with Gq/11 which then forms complex (PI3K). A signaling cascade then follows leading to prevents its apoptosis and increases insulin secretion with phosphatidylinositol-4,5-bisphosphate 3-kinase inIn pancreas,glucose dependent GLP-1 promotes manner beta-cell by producing differentiation, cyclic insulin sensitivity as depicted in Figure 4. GPR120 is GLUT translocation for glucose uptake, thus enhancing also involved in inhibition of macrophage induced tissue reduces insulin resistance in pancreas, adipose, liver and muscleadenosine tissues. monophosphate Particularly in hepatic (cAMP) and [107]. muscle GLP-1 cells, associatesinflammation with and the reducing stimulated insulin GPR120 resistance. which Binding together of protein kinase (AMPK) activity and fatty acid oxidation participateomega-3-fatty in acid downstream stimulates GPR120. signaling Then mechanismβ-arrestin2 (FigureGLP-1 increases 5). 5' adenosine monophosphate-activated asinhibiting illustrated lipopolysaccharides in Figure 4. When (LPS) GPR120 and tumor is activated necrosis byfactor unsaturated (TNF-α) induced long chain inflammatory fatty acids, signaling it promotes process the arePlant no stanols reports and on the sterols effect are of beneficialsaturated infat, reducing dietary cholesterolLDL cholesterol and transfat in diabetic among subjects. diabetic However, populations. there a polypeptide Cholesterol rich high fat diet tends to increase adipose hormonerelease of which incretin potentiates glucagon-like glucose peptide-1 stimulated (GLP-1) insulin in tissue at various parts of body and activates innate gut enteroendocrine L-cells. GLP-1 is immune system [108]. Generally, it has been shown 1 enables nutrient homeostasis in both pancreatic that, such diet not only associated with obesity but also secretion, thus lowering the plasma glucose level. GLP- Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 62 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75

Figure 5: Step-wise illustration of dietary cholesterol metabolism in T2DM. Dietary cholesterol is taken up by intestinal epithelial cells. Intracellular esterification of cholesterol by Acyl-CoA cholesterol acyltransferase (ACAT) forms cholesterol esters. Esterified cholesterol is grouped into chylomicrons which are transported to liver cells. Hepatic cholesterol forms very low density lipoproteins (VLDL) which are acted upon by lipoprotein lipase forming intermediate-density lipoprotein (IDL) and subsequently low density lipoprotein (LDL). Oxidized LDL enters beta cell through low density lipoprotein receptor (LDLR) by endocytosis. Under hypercholesterolemic condition, the liver X receptor (LXR) and ATP-binding cassette protein (ABCA1) gets inhibited which are responsible for efflux of cholesterol. The accumulated cholesterol leads to cellular stress followed by beta cell apoptosis and also activates neuronal nitric oxide synthase (nNOS). nNOS produces nitric oxide (NO) from L-arginine. NO production leads to s-nitrosylation of glucokinase and inhibits glucose-stimulated insulin secretion from pancreatic beta cells. causes altered endocrine and metabolic regulations like The pathway of cholesterol metabolism has been diabetes, dyslipidemias, cardiovascular diseases, hepatic illustrated in Figure 6. Dietary cholesterol enters the mediate increase of white adipose tissue and related immunesteatosis response and cancer contributes [109-116]. to Inthe case cornerstone of T2DM, effect diet mucosal cells in the form of unesterified sterol and is esterified before incorporation into chylomicrons in disease pathology [108,112]. Association between a regulatory factor in cholesterol absorption [120]. and secretion to lymph. This esterification process is diabetes mellitus and hypercholesterolemia, which is Two enzyme systems have been described for this regarded as one of the most important factors involved that cholesterol esterase (EC 3.1.1.13) secreted from in the acceleration of atherosclerosis in diabetic patients theesterification pancreas inpenetrates the intestine. into Early the studiesintestinal demonstrated absorptive plasma cholesterol levels in diabetic rats are notably high [117]. Researchers in this field have observed that reversal of the hydrolytic reaction [121]. Furthermore, cells and catalyzes cholesterol esterification through a there have been extensive studies on the catabolism of acyltransferase (ACAT, EC 2.3.1.26) are also important plasmacompared lipoproteins with non-diabetic in diabetic animalsanimals [119], [118]. only Although some several reports have indicated that acyl-CoA: cholesterol have dealt with alterations in cholesterol absorption. from the intestine [122]. An evident increment of The small intestine plays a key role in cholesterol plasmain controlling cholesterol the transportlevels with of esterifiedthe accumulation cholesterol of metabolism because it is a site for the absorption of remnant lipoproteins in diabetic animals fed with a dietary cholesterol. ad libitum has been reported

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Figure 6: Schematic representation of dietary fiber derived short chain fatty acids (SCFA) effects on glucose and insulin metabolism. Microbial fermentation of dietary fiber in colon yields SCFA which activates G-protein coupled receptors (GPR43 and GPR41). Subsequently, the Enteroendocrine L cells secrete gut hormones namely, glucagon like peptide (GLP-1) and pancreatic peptide YY (PYY). Various physiological effects of GLP-1 and PYY in different organs are illustrated. GLP-1 binds to G-protein coupled GLP-1 receptor in pancreatic islets allowing insulin gene expression, translation and proinsulin synthesis and insulin secretion. GLP-1 stimulates increased production of insulin and decrease in glucagon secretion thus promoting glucose uptake. In liver, SCFA decrease FA synthesis and promote FA oxidation. In adipose tissue, SCFA promote secretion of leptin that suppresses apetite and increase satiety. In liver and muscle cells, SCFA promote 5' adenosine monophosphate-activated protein kinase (AMPK) activation causes increased expression of PPARα genes involved in FFA oxidation leading to insulin sensitivity and glucose homeostasis. (↑) mark indicates up-regulation and (↓) mark indicates down regulation. previously. The precise mechanism for diabetic hypercholesterolemia is unclear. Young et al. reported complex are found inhibited and as a result, cholesterol that hyperphagia in diabetes plays an important role in receptor (LXR)-ATP binding cassette protein A1 (ABCA1) this phenomenon [123]. cells are prone to cellular stress and related cellular toxicityefflux has [128]. been Such found cholesterol clogged [127]. mediated Cholesterol cellular loaded stress Accumulation of cholesterol with dietary fat acts and apoptosis mediated cell death has been found in as noxious stimuli and also held responsible for activation of innate immune system [124]. Chemotactic Somepancreatic adipocyte β cells derived [129]. cytokines (adipokines) has been cytokinesinflammation, or chemokines an immune are response released as which an immediate indicates found in altered levels during hypercholesterolemic diet response that attracts leucocytes and initiates leucocytes mediated defense orchestration [125]. It has been shown Adiponectininduced inflammation, and Resistin which are arethose playing molecules, determining having role in insulin resistance and T2DM [130,131]. Leptin, activatethat minimally certain cytokines modified like or tumor oxidized necrosis LDL factor cholesterol alpha activates toll-like receptors-4 (TLR-4), which is known to diversified functional contribution in T2DM [132,133]. During inflammatory processes, increasing levels of (TNFα),initiates macrophagemonocyte and inflammatory macrophage proteinaccumulation 2 (MIP-2), and interleukins (IL-1, IL-6) and lipopolysaccharides (LPS) and monocyte chemo attractant protein 1 (MCP-1), influences an uprising of leptin, indicating its protective thepotential protective against pathway inflammatory [134]. Adiponectin response. is crucial Leptin most also notinfluences only been rapid reported process in T2DM of inflammation but also in [126].the case LDL of adipokine,modulate the having activity multiple of T-cells functional and thereby contributions potentiates in mediated immune activation and inflammation has the pathology of T2DM. It increases fatty acid oxidation, decreases glucose synthesis in the liver and also involved atherosclerosis [127]. Experimental reports have shown in the feedback sensitivity of insulin receptor and that, inflammatory activation of TLR 3 or 4 leads to cholesterol accumulation in cell and in such cases Lipid X Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 64 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75 thereby shows protective aids against insulin resistance either protein or GI or their interaction effect on glucose either through modulating transcription factor, like or insulin response in overweight adults [143]. via IDF improves insulin sensitivity and reduced diabetes peroxisome proliferator-activated receptor α (PPARα) or associated LPS activation with positive [132,133]. feedback Resistin, system. another It also adipokine plays an to decreased risk of mortality among diabetic found in increasing levels in inflammatory state is important role in insulin resistance and cardiovascular populationrisk. Intake and of high particularly levels of dietaryamong fiberdiabetic was people linked dysfunction [135,136]. with normal weight; higher sugar intake was associated

inversely associated with insulin resistance. Microbial microdomains of plasma membrane is promoted by with high mortality risk [54]. Total dietary fiber is The formation of lipid rafts-cholesterol enriched chain fatty acids (SCFA) such as acetate, propionate and cholesterol concentration of media causes accumulation fermentation of dietary fiber in the colon produces short ofaccumulation excess cholesterol of membrane in membrane cholesterol in mouse [137]. insulinoma High butyrate which reduce hepatic glucose output. SCFA such as propionic acid reduces hepatic gluconeogenesis rafts resulted in nicotinamide adenine dinucleotide (MIN6) cells. High cholesterol induced formation of lipid effects of SCFAs in T2DM have been schematically generation of reactive oxygen species (ROS) has been representedand stimulates in Figure glycolysis. 5. SCFAs The positiveactivate andfree beneficialfatty acid phosphate (NADPH) oxidase activation mediated Gi/o pathway leading to 2+ ions. This leads bysuggested the death to bereceptor the reason ligands of LDLsand apoptotic loading inducedfactors receptor (FFAR2). FFAR2 couples to both the Gq and apoptosis of MIN6 cells. Lipid raft clustering is stimulated influx of Ca cellular dysfunction [138]. It is also suggested that the coupledto the productionreceptor resulting of glucagon in the activation like peptide of adenylate (GLP-1) resulted in activation of NADPH oxidase and consequent by enteroendocrine L cells. GLP-1 binds to G-protein to promoted formation of lipid raft, resulted in the (cAMP) gets enhanced leading to intracellular signaling LDLs loading induced apoptosis of MIN6 cells is due ultimatelycyclase. Subsequently resulting in cyclicinsulin adenoside secretion. monophosphate impedesactivation insulin of NADPH secretion oxidase due and to hence association generation of ion of ROS [139]. However, reduction of membrane cholesterol Role of micronutrients attachment protein receptor (SNARE) proteins with the Chromium is present in the form of CrCl in various food channels and soluble N-ethylmaleimide-sensitive factor 3 sources at microgram level (Table 1). Vegetables such as broccoli and whole cereals are rich sources of chromium. Rolerafts inof β-cellscarbohydrates [140]. Cefalu et al. have conducted an elaborated review on the effect of chromium on blood glucose and found The source of carbohydrates is being considered as more important than th improves insulin sensitivity [21]. Suksomboon et al. also Carbohydrates from fruits, vegetables, whole grains observedthat chromium that chro reducesmium blood supplementation glucose level, reduced HbA1c andthe e quantity for management of diabetes. ohydrates. Fructose intake occurs in cereal grains and green leafy vegetables. It has fromare considered naturally occurring more beneficial foods or in thefruits management is considered of positiveHbA1c [144]. effects Iron on isbeta an cell essential functioning micronutrient and reduction which gooddiabetes for thanblood refined glucose carb management than isocaloric sucrose or starch. The property of increased viscosity insulin sensitivity since it is a cofactor in more than 200 metabolicof inflammatory reactions response. and is anMagnesium important is metalloenzyme important for reduces the bioavailability of macronutrients and thus in phosphorylation and dephosphorylation reactions in reducesand gel formationpost prandial due bloodto the glucosepresence level. of soluble Prospective fiber glycolysis. Green leafy vegetables, cereals and legumes cohort studies have emphasized that insoluble dietary are rich sources of magnesium (Table 2). Akter et al. have reported that dietary magnesium rather than associated with reduction in risk of diabetes rather than fiber (IDF) from cereals and whole grains is consistently serum magnesium concentration was negatively correlated with homeostatic model assessment of soluble dietary fiber (SDF) [141]. In whole grain sorghum insulin resistance in healthy adults [145]. Protein kinase flour, the IDF content was 25% and the corresponding in insulin signaling cascade and secretion of insulin GI was 77 (Table 2). In water melon even though the is dependent on magnesium. In the present review, it IDF was comparatively lesser, the GI was 76 because of magnesium, exhibited GI of 28 which can be considered ithigher was GL.observed Coconut thatflour intakewith less of than carbohydrates 55 GI was found and was observed that barley, containing 79 mg/100 g of to contain 0.3% of SDF. Based on 31,641 participants, magnesium was negatively associated with incidence in bicarbonate dependent reactions, modulates of diabetes whereas, dietary GI and diabetes were glucokinaseas low (Table activity 2). Biotinand suppresses functions gluconeogenesis as a coenzyme

Makris et al. have observed that there was no effect of was found to be densely distributed in brown rice, barley positively associated with starch intake [142]. However, by limiting phosphoenolpyruvate carboxykinase. Biotin Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 65 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75 and banana among which barley was found to elicit least from dietary resources by vulnerable population. Intake GI of 28 (Table 2). In combination with chromium, biotin of dietary bioactive components lessens the burden of medication especially in chronic disease conditions variantsreduces of fasting insulin glucose resistant level, genes HbA1c, with the cholesterol nutrients and course for a permanent cure and the medication needs foundLDL [146,147]. that T2DM Hong risk was et al. higher studied in subjects the interaction with high of such as diabetes where there is no definitive medication energy and low calcium intake [148]. Myers et al. studied the implications of zinc and insulin signaling on T2DM Phyticto be continued acid (inositol life-long. hexakisphosphate), a cyclic acid, is the main storage form of phosphorus in seeds. The salt form of phytic acid is termed as phytate. Phytic acid pancreas[149]. Zn whichis a component transports in zinczinc intotransporter-8 insulin secretory (ZNT8) occurs mostly in cereal grains, nuts and legumes. Among granuleswhich is [150,151]. predominantly Other present transporters in beta-cells such as of ZIP6 the cereals and millets, the phytic acid content ranges from

[152,153]. is one of the rich sources of phytic acid containing as high and ZIP7 also have zinc that control insulin signaling as0.06 9.42 g to g/100 7.3 g/100 g on g dry on dryweight weight basis. basis Among [162]. legumes, Almond its content ranges from 0.22 to 2.38 g/100 g (Table was associated with alleviation of oxidative stress 1). It functions as a strong chelating agent for divalent Vitamin E intake has beneficial effect on T2DM as it bioavailability of metabolically important minerals such that there are no substantial evidences to prove that ascations iron, andzinc consequentlyand calcium. hasSome the of potential the divalent to limit cations the supplementationin pancreatic β-cells of vitamin [154]. E Xu causes et al. improvement have observed in are cofactors of enzymes and transporter proteins of glucose. Phytic acid also chelates calcium which is the [155]. In the present review, highest content of vitamin HbA1c and fasting blood glucose level in T2DM subjects cofactor in the enzyme alpha amylase thus inhibiting its E was found to be in pumpkin seed oil followed by activity and reducing glycaemic propensity. Therefore, brown rice (Table 2). Vitamin C occurs densely in citrus phytic acid indirectly acts on glucose metabolism by inhibiting synthesis and glucose uptake. Phytic acid also binds with starch and starch associated proteins fruits is helpful in insulin secretion by virtue of its anti- to reduce triglycerides. In a study conducted on 42 thus hindering their digestion and exerting glycaemic healthyoxidative subjects, effect [156,157]. Sur et al. Vitaminhave observed C has thethat potential vitamin control [14]. When phytic acid was fed to chemically D level was negatively associated with fasting blood induced T2DM rats at the rate of 650 mg/kg for 28 days, sugar and postulated that hypovitaminosis of vitamin D fact decreased. A dose dependent inhibition of alpha studies and randomized controlled trials, Mitri et al. glucosidaseit was found and that reduction the glucose of levelalpha and amylase HbA1c haveactivity in havemay leadobserved to T2DM that [158]. individuals Based onwith observational higher vitamin cohort D was found. Therefore, phytate helps in lowering blood status are less prone to development of T2DM [159]. glucose level either by binding with glucose releasing The vitamin D content of chickpea was found to be as starch or by inhibiting the enzymes involved in starch high as 1.93 mcg/100 g with corresponding GI of chick digestion. This is additionally corroborated by the fact pea being 28 (Table 2). The GI and starch intake were that among 15 different food sources, the phytic acid inversely related to intake of micronutrients and lower GI was one of the predictors for desirable micronutrient etcontent al. also was observed significantly that sodiumand negatively phytate correlated at the rate (r=- of 2%0.8; ofP ≤starch 0.05) portionto their reducedrespective in glycaemicvitro digestion indices. by Yoon50% Bioactiveprofile among compounds pregnant and women [55]. [163]. Therefore, phytic acid has immense potential in regulation of glycaemic condition. In this review, it Dietary bioactive components have important role in the was found that barley having phytic acid content of basic human metabolism and also in disease condition. 386 mg/100 g elicited a GI of 28 whereas kidney beans containing upto 481 mg/100 g of phytic acid could elicit tion and interaction These components exert their influence by virtue of considered as low GI foods. a GI of 24 (Table 2). Both these food sources can be propertiestheir unique act structuralagainst the configuramanifestation and progression ofwith disease/disorder bio-molecules. Dietary confers components improvement with in bioactive health Some of the rich dietary source of glycine betaine outcomes and stabilizes basic metabolism [160,161]. includes spinach, whole wheat, and marine invertebrates e functions as intracellular osmolyte. several chronic disease conditions with their modulatory [164]. Betain effectBioactive on dysregulated components aremetabolic beneficial pathways and effectivewhich are in beta cells from excess of glucose molecules in the blood highly relevant to disease progression and treatment. streamBetaine in exhibits the diabetic a protective condition effect (Table on the1). pancreaticIncreased The increased preference for and recent focus on level of betaine was previously found to be associated biologically sourced active components is because they with higher insulin sensitivity and lower risk factors of can be consumed over a prolonged period of time devoid of any adverse side effects and can be easily accessed diabetes such as triglycerides and adiposity (Figure 7). Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | SeptemberBetaine 2018 was also found to be effective in normalization66 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75

Figure 7: Promoting and inhibitory effect of nutrients on diabetic features viz., (1) Blood glucose/Glycaemic index (2) Glycated Haemoglobin (HbA1c) (3) Insulin resistance and (4) Insulin secretion. Down arrow (↓) represents inhibitory effect while up-arrow (↑) represents promoting effect of the nutritional components on the corresponding diabetic features. Interrelation among diabetic features with T2DM was linked by connecting arrows. of gluconeogenesis and glycogenolysis in pertain to in vitro or animal model studies [169]. Recent

HepG2 cells. rat pancreatic beta cells and regulates carbohydrate isLever a strong et al. haverisk factorobserved in diabetes that enhanced [165]. levelTiihonen of betaine et al. studies show that morin has anti-oxidative capacity in havemetabolite, reported an analog-that betaine trimethylamine-N-oxide has good bioavailability (TMAO) et al. have demonstrated that supplementation of among Asian populations and was effective in improving metabolic enzyme activities [170,171]. Seyyedebrahimi oxidative effect in T2DM patients in a randomized, double that the plasma concentration of glycine betaine was at the rate of 800 mg/day showed anti- the liver metabolism [166]. Lever et al. have reported not correlated to glycosylated haemoglobin, however, , salidroside and cryptotanshinone have been reportedblind, placebo to exert controlled AMPK mediatedclinical trial promotive [172]. Berberine, effect on renal excretion was highly significant among diabetic fractions from rice bran showed glycaemic control [62]. patients [167]. On the contrary, Dellow et al. reported with plasma glucose and glycated haemoglobin [168]. Inglucose a recent uptake review, by muscle resveratrol and adipose has been tissue reported while fiber to that excretion of betaine was significantly correlated has been shown to have inhibitory effect on improve metabolic functioning in T2DM patients [173]. Morin is a natural biflavonoid compound that has anti-diabeticJournal of Research property; in Medical however, and Dental mostScience of | Vol. the 6 | reportsIssue 5 | September 2018 67 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75 alpha glucosidase enzyme activity by hydrophobic and

pathogenesis [186]. MBL has also been associated with electrostatic interaction with them [174]. Alkylresorcinols,pathogenesis of vascular lectins and complications phytic acid in are T2DM able [187].to bind occur in cereals. Structurally, it is an arabinofuranosyl substitutedArabinoxylans polymer are non-starch of xylose. polysaccharidesIntake of arabinoxylan which limiting its activity. Another enzyme involved in has been associated with lower level of serum glucose to α-amylase (an enzyme involved in starch digestion), particularly in impaired glucose tolerance condition be inhibited by phenolic acids and alkylresorcinols. Absorptioncarbohydrate of digestionglucose isfrom α–glucosidase, the intestines which to canthe bloodstream goes through sodium dependent glucose enzymes[175] and and metabolic impedes control absorption of blood of glucose glucose in inthe people small intestinewith T2DM (Table [176]. 1). The Arabinoxylans water extracts limits of arabinoxylan access to border membrane. Ferulic and chlorogenic acids exhibit from wheat bran and aleurone layers have shown antransporter ability to (SGLT1)block this localized transporter, in the limiting intestinal the rate brush of antiglycaemic properties due to inhibition of alpha absorption. Therefore, phenolic acids are important in the modulation of glucose uptake from blood to muscle SCFA production such as cells (Table 1). Triterpene acid, generally found in SCFAglucosidase decrease activity gluconeogenesis [177]. Arabinoxylan in liver thus controlling stimulates medicinal plants was also found to have improving effect butyrate and acetate [178]. on T2DM [28]. that consumption of arabinoxylan crackers have shown blood sugar level (Figure 7). Clinical trials have shown On an overall basis, the nutritional components derived from different food sources executes their physiological beneficial effect on glycaemic control among overweight functions in a manner that regulate the glycaemic effects subjects [179]. Lu et al. [176] have demonstrated that in terms of blood glucose level (GI), glycated haemoglobin supplementation of arabinoxylan rich fiber at the rate level, Insulin secretion and Insulin resistance. A large thatof 15 long g per term day significantlyintake of long improves chain arabinoxylans glycaemic control has number of nutrients, comprising of gross nutrients thein T2DM.potential Based to reinstate on human glucose trials, and it insulin was established metabolic were implicated directly in regulation of blood glucose was also found to improve insulin sensitivity. Among levelsuch asand dietary comparatively fiber, proteins, fewer carbohydratesnumbers of nutrients, and fats, thefunctions cereals in containing T2DM patients arabinoxylan, [180]. Similarly lowest GIbeta-glucan of 29 was mostly comprising of bioactive components and amino observed for rye (Table 2). acids, were associated directly with insulin metabolism that includes insulin resistance and sensitivity (Figure Alkylresorcinols are phenolic lipids that are catabolized in the liver into two different metabolites. Sun et al. bioactive components are highly relevant for prevention have reported that plasma alkylresorcinol metabolite and7). Therefore,alleviation itof canchronic be suggestedT2DM while that a most diets optimal rich in combination of carbohydrate, fat and protein can level was inversely associated with T2DM and be chosen as a diet for symptomatic reduction of impaired3-(3,5-dihydroxyphenyl)-1-propanoic glucose metabolism among Chinese acid (DHPPA) people hyperglycaemia. [181]. Alkylresorcinols have the capacity to bind to alpha amylase and alpha glucosidase thus limiting CONCLUSIONS studied the plasma alkylresorcinol association with risk of T2DM and After digestion by the action of gastric enzymes, the observedtheir activity. that consumption Biskup et al. of have whole grains composed food matrix along with glucose and several nutritional of substantial amount of rye is associated with lower components are absorbed into the blood stream. These risk of T2DM among Scandinavian population [182] and components have different effects on the glucose level alkylresorcinols metabolites in plasma are proportional as well as insulin secretion and functioning. Protein and fat metabolism were found to have a strong association with glucose and insulin metabolism to rye fiber intake [183]. and act in synergy to regulate and maintain optimal with the ability to bind to carbohydrates without Lectins or haemaglutinins are a large group of proteins information of several nutrients that have been the potential causes for instigation of insulin dependent blood glucose level. This review collates the scientific diabeteschanging [185]. their structuresIn this review, [184]. it Lectins was noted can bethat one soy of glycaemic regulation. Additionally, their individual and synergisticidentified androles characterizedin human metabolism for their as influencewell as their on mg of lectins could elicit GI of 15 and 36, respectively, site of action can be interpreted. Some of the nutrients whichbeans andwere chick comparatively peas containing lower 87 than HU/mg GI values and 180 elicited HU/ by either wheat, potato or banana that contain lesser ibility level onsuch the as glucose dietary release fiber and rate. available Micronutrients carbohydrates and bioactive act on a dose dependent manner at the bio-access blood glucose concentration of lectins ranging from 1.3 HU/mg to release, insulin metabolism and action at the metabolic patients13 HU/mg with (Table nephropathy 2). Guan and et suggested al. have observedits role in thatthe level.components Nutrients exert such their as fatty influence acids, vitaminon the D, potassium, mannose binding lectins (MBL) were elevated in T2DM Journal of Research in Medical and Dental Science | Vol. 6 | Issue 5 | September 2018 68 Prasad VSS et al J Res Med Dent Sci, 2018, 6 (5):52-75

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