Prediabetic Rats Research Articles

Peri-renal adipose inflammation contributes to renal dysfunction in a non-obese prediabetic rat model: Role of anti-diabetic drugs

Diabetic nephropathy is a major health challenge with considerable economic burden and significant impact on patients’ quality of life. Despite recent advances in diabetic patient care, current clinical practice guidelines fall short of halting the progression of diabetic nephropathy to end-stage renal disease. Moreover, prior literature reported manifestations of renal dysfunction in early stages of metabolic impairment prior to the development of hyperglycemia indicating the involvement of alternative pathological mechanisms apart from those typically triggered by high blood glucose. Here, we extend our prior research work implicating localized inflammation in specific adipose depots in initiating cardiovascular dysfunction in early stages of metabolic impairment. Non-obese prediabetic rats showed elevated glomerular filtration rates and mild proteinuria in absence of hyperglycemia, hypertension, and signs of systemic inflammation. Isolated perfused kidneys from these rats showed impaired renovascular endothelial feedback in response to vasopressors and increased flow. While endothelium dependent dilation remained functional, renovascular relaxation in prediabetic rats was not mediated by nitric oxide and prostaglandins as in control tissues, but rather an upregulation of the function of epoxy eicosatrienoic acids was observed. This was coupled with signs of peri-renal adipose tissue (PRAT) inflammation and renal structural damage. A two-week treatment with non-hypoglycemic doses of metformin or pioglitazone, shown previously to ameliorate adipose inflammation, not only reversed PRAT inflammation in prediabetic rats, but also reversed the observed functional, renovascular, and structural renal abnormalities. The present results suggest that peri-renal adipose inflammation triggers renal dysfunction early in the course of metabolic disease.

The Haemolytic Changes During Progression of Pre-Diabetes to Type 2 Diabetes in a High-Fat High-Carbohydrate Diet-Induced Pre-Diabetic Rat Model

The Haemolytic Changes During Progression of Pre-Diabetes to Type 2 Diabetes in a High-Fat High-Carbohydrate Diet-Induced Pre-Diabetic Rat Model

Polyherbal Formulation (PDBT Capsules) Containing Extracts of Ayurvedic Plants for Treatment of Prediabetes

In Prediabetes blood sugar levels are found to be higher than normal levels. It is considered as pre stage of diabetes as people with prediabetes, if remain undiagnosed, have chances of developing type 2 diabetes. Studies show that if diabetes is treated in the prediabetic stage, it results in complete cure of diabetes. The objective of the present study was to investigate effect of PDBT capsules containing extracts of well-known Ayurvedic plants such as <i>Zingiber officinale, Tinospora cordifolia, Pterocarpus marsupium, Gymnema sylvester</i>, and <i>Momordica charantia</i> on prediabetic condition induced in Wistar rats. High fat fructose diet was fed to male Wistar rats to induce prediabetes. After induction on 11^th week of study, the prediabetic rats were divided in different groups. Treatment groups received Pioglitazone (3 mg/kg) (standard control), test formulation, PDBT capsule (200mg/kg) (test group) along with high fat fructose diet. Normal diet control group received normal diet and high fat fructose diet control group received only high fat fructose diet. The different biochemical parameters, blood glucose levels and body weights were monitored. Animals were sacrificed at the end of study period. Histopathological studies on the major organs such as liver, kidney, pancreas was performed. High fat fructose diet induced of prediabetes in rats. Significant decrease in levels of fasting blood glucose and biochemical parameters in treatment groups was observed. The histopathological study showed no abnormalities. The present research show that PDBT capsules can be efficiently used in prediabetes treatment. Hence, PDBT capsule can be a potential agent for the treatment of prediabetes.

The dysregulation of the hypothalamic\u2013pituitary\u2013adrenal axis in diet-induced prediabetic male Sprague Dawley rats

BackgroundAltered function of the hypothalamic–pituitary–adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model.MethodsSprague Dawley Rats were randomly divided into non-pre-diabetic group (NPD) and pre-diabetic group (PD) (n = 6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, glucose handling using the Homeostasis Model Assessment indices, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were also measured.ResultsImpaired glucose handling in the PD group as well as increase in corticosterone was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed using the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group.ConclusionThese observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

Abstract 15180: Myeloid Differentiation Factor 2 Inhibitor Improves Left Ventricular Function And Heart Rate Variability Via Attenuating Cardiac Mitochondrial Dysfunction In Pre-diabetic Rats

Introduction: Systemic inflammation is known as a key mediator of left ventricular (LV) dysfunction in pre-diabetic models including obese-insulin resistance. In obese rats, lipopolysaccharide activates myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex, leading to systemic inflammation. Previously, MD2 inhibitor L6H21 (20 mg/kg) was shown to effectively reduce systemic inflammation in obese mice. However, its potential benefits on the heart and the underlying mechanisms in pre-diabetic obese-insulin resistant rats are unknown. Hypothesis: L6H21 exerts cardiometabolic protection in pre-diabetic rats by improving LV function and heart rate variability (HRV) via reducing cardiac mitochondrial dysfunction. Methods: Male Wistar rats were fed either a normal diet (n=8) or high-fat diet (HFD, n=40) for 12 weeks. In HFD group, rats were divided into 5 groups (n=8/group): 1) vehicle (1% Na-carboxymethyl cellulose), 2) metformin (300 mg/kg, positive control), 3-5) L6H21 at 10, 20, and 40 mg/kg. After 4 weeks of treatments, LV function and HRV were examined. Heart tissue was assessed for mitochondrial function. Results: Pre-diabetic rats had impaired glucose tolerance, depressed HRV, and decreased LV ejection fraction (LVEF), indicating cardiac autonomic imbalance and LV dysfunction. Cardiac mitochondrial dysfunction was also observed, shown by increased mitochondrial ROS levels, mitochondrial depolarization, and mitochondrial swelling. Although L6H21 at 20 and 40 mg/kg improved insulin sensitivity, cardiac autonomic balance, LV function, and mitochondrial function, L6H21 at 40 mg/kg exerted the highest cardioprotective effects, compared to metformin, in pre-diabetic rats by restoring LV function, HRV, and cardiac mitochondrial function (Fig) . Conclusions: L6H21 exerted cardiometabolic protection in pre-diabetic rats by improving insulin sensitivity and cardiac mitochondrial function, leading to restoring LV function.

Abstract 15178: Mitochondrial Dynamic Modulators Mitigates Mitochondrial Dynamic Index, Biogenesis and Metabolic Impairments in Prediabetic Rats With Cardiac Ischemia-reperfusion Injury

Introduction: Long-term exposure to high-fat diet (HFD) caused obesity, which not only was positively associated with cardiovascular disorders but also had a negative impact on the outcome of acute myocardial ischemia-reperfusion (I/R) injury. Uncontrolled fission and diminished fusion of cardiac mitochondria augment the impairment of mitochondrial biogenesis and metabolism which have been implicated in metabolic diseases and I/R injury pathology. Since cardioprotective efficacy of acute administration of mitochondrial fission inhibitor (Mdivi-1) and fusion promoter (M1) have previously been reported, the effects of chronic treatment with both modulators on cardiac mitochondrial dynamics, biogenesis and lipid metabolism in prediabetic rats subjected to cardiac I/R injury have never been elucidated. Hypothesis: Chronic treatment of Mdivi-1 and M1 after acute myocardial I/R improve mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats. Methods: Male Wistar rats (n=18) were fed with HFD. After 12 weeks, all rats were randomly divided into: 1) HFV (Vehicle, 0.1% DMSO), 2) HFMd (Mdivi-1, 1.2 mg/kg), and 3) HFM1 (M1, 2 mg/kg) with intraperitoneal injection for 14 days. Then, all rats underwent 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 120 minutes. The expression of mitochondrial dynamics (p-Drp1 ser616 per Mfn2 ratio or dynamic index), biogenesis (PGC1- α) and lipid metabolism (CPT1) proteins from ischemic area of heart were determined. Results: Chronic treatment of Mdivi-1 and M1 similarly improved cardiac mitochondrial dynamic index (p-Drp1 ser616 per Mfn2 ratio), increased PGC1-α and CPT1 expression levels, when compared to HFV (Fig). Conclusions: Modulating mitochondrial dynamics by chronic treatment of Mdivi-1 and M1 improved cardiac mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats following acute myocardial I/R injury.

Not only metformin, but also D-allulose, alleviates metabolic disturbance and cognitive decline in prediabetic rats

ABSTRACT Background Prediabetes can be characterized as obesity with metabolic disturbance, leading to cognitive decline and brain pathologies. D-allulose administration in obese animals decreased metabolic disturbance. However, the comparative effects of D-allulose and metformin on cognition and brain functions in the diet-induced prediabetic condition are unclear. We assume that both D-allulose and metformin equally restore cognition and brain functions in prediabetic rats to an equal extent. Materials and methods Fifty-six rats were randomly divided into two groups: a control and diet-induced prediabetic group which had received a normal diet (ND) and a high-fat diet (HFD) for 24 weeks, respectively. After dietary protocol had been followed for 12 weeks, ND rats were given solely drinking water daily for 12 weeks. HFD-prediabetic rats randomly received drinking water with either D-allulose (1.9 g/kg/day of D-allulose) or metformin (300 mg/kg/day of metformin) for 12 weeks. Following this, cognition and brain parameters were determined. Results Brain oxidative stress, mitochondrial dysfunction, microglial hyper-activation, apoptosis, brain insulin insensitivity, hippocampal synaptic dysfunction, and cognitive decline were observed in prediabetic rats. D-allulose and metformin equally attenuated brain oxidative stress, brain mitochondrial ROS production, hippocampal apoptosis, brain insulin insensitivity, hippocampal synaptic dysfunction, resulting in improved learning process in prediabetic rats. Metformin conferred greater advantage on the amelioration of brain mitochondrial dysfunction and brain microglial hyper-activation than D-allulose, resulting in improvement in both learning and memory processes in prediabetic rats. Conclusions Not only metformin, but also D-allulose, has beneficial effects on the enhancement of brain function and cognition in prediabetic condition.

Hyperbaric oxygen therapy attenuates D-galactose-induced-age-related cardiac dysfunction through mitigating cardiac mitochondrial dysfunction in pre-diabetic rats

Abstract Background D-galactose (D-gal) induced ageing has been shown to exacerbate left ventricular (LV) dysfunction via worsening of apoptosis and mitochondrial dysfunction in the heart of obese rats. Hyperbaric oxygen therapy (HBOT) has been demonstrated to exert anti-inflammatory and anti-apoptotic effects in multiple neurological disorders. However, the cardioprotective effect of HBOT on inflammation, apoptosis, LV and mitochondrial functions in D-gal induced ageing rats in the presence of obese-insulin resistant condition has never been investigated. Purpose We sought to determine the effect of HBOT on inflammation, apoptosis, mitochondrial functions and LV function in pre-diabetic rats with D-gal induced ageing. We hypothesized that HBOT attenuates D-gal induced cardiac mitochondrial dysfunctions and reduces inflammation and apoptosis, leading to improved LV function in pre-diabetic rats. Methods Forty-eight male Wistar rats were fed with either normal diet or high-fat diet for 12 weeks. Then, rats were treated with either vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-gal groups (150 mg/kg/day, SC) for 8 weeks. At week 21, rats in each group were equally divided into 6 sub-groups: normal diet fed rats treated with vehicle (NDV) sham, normal diet fed rats treated with D-gal (NDDg) sham, high fat diet fed rats treated with D-gal (HFDg) sham, high fat diet fed rats treated with vehicle (HFV) + HBOT, NDDg + HBOT and HFDg + HBOT. Sham treated rats were given normal concentration of O2 (flow rate of 80 L/min, 1 ATA for 60 minutes), whereas HBOT treated rats were subjected to 100% O2 (flow rate of 250 L/min, 2 ATA for 60 minutes), given once daily for 2 weeks. Results Under obese-insulin resistant condition, D-gal-induced ageing aggravated LV dysfunction (Fig 1A) and impaired cardiac mitochondrial function, increased cardiac inflammatory and apoptotic markers (Fig 1B). HBOT markedly reduced cardiac TNF-α level and TUNEL positive apoptotic cells, and improved cardiac mitochondrial function as indicated by decreased mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, resulting in the restoration of the normal LV function in HFV and NDDg rats, compared to sham NDDg rats. In addition, in HFDg treated rats, HBOT attenuated cardiac TNF-α level, TUNEL positive apoptotic cells and cardiac mitochondrial dysfunction, compared to sham HFDg rats, leading to improved cardiac function as indicated by increased %LV ejection fraction (LVEF) (Figure 1). Conclusion HBOT efficiently alleviates D-gal-induced-age-related LV dysfunction through mitigating inflammation, apoptosis and mitochondrial dysfunction in pre-diabetic rats. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. The National Science and Technology Development Agency Thailand, 2. Thailand Research Fund Grants

Cardiopreventive effects of mitochondrial dynamics modulators in pre-diabetic rats subjected to cardiac ischaemia-reperfusion injury

Abstract Background Chronic exposure to a high-fat diet (HFD) consumption causes alteration of cardiac mitochondrial dynamics and function, leading to the abnormal left ventricular (LV) function. Since excessive mitochondrial fission and reduced mitochondrial fusion are correlated with both obesity and myocardial ischaemia, targeting mitochondrial fission and fusion could be an effective cardioprotective strategy. We previously showed that acute inhibition of mitochondrial fission and promotion of mitochondrial fusion exerted cardioprotection in obese rats. However, the chronic treatment with mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) in pre-diabetic rats subjected to cardiac ischaemia-reperfusion (I/R) injury has never been investigated. Purpose We investigated the cardiopreventive effects of chronic Mdivi-1 and M1 treatment in pre-diabetic rats with cardiac I/R injury on infarct size, mitochondrial function, and LV contractility. Methods Wistar rats (n=32, male) were fed with HFD for 12 weeks, then randomly divided into: 1) HFV (Vehicle, 0.1% DMSO), 2) HFMdivi1 (Mdivi-1, 1.2 mg/kg), and 3) HFM1 (M1, 2 mg/kg) with intraperitoneal injection. After 2 weeks of drugs administration, all rats underwent 30 min of left anterior descending coronary artery occlusion followed by reperfusion for 120 min. LV function was monitored throughout the experiment. At the end, the heart was removed to determine infarct size and mitochondrial function. Results Chronic treatment with Mdivi-1 and M1 similarly showed a decrease in mitochondrial reactive oxygen species and infarct size, leading to an improvement in LV function in HFD rats, as indicated by increased ejection fraction, when compared to HFV rats (Figure). Conclusion Mitochondrial fission inhibitor and fusion promoter exerted similar efficacy in protecting pre-diabetic rat hearts against cardiac I/R injury through attenuating mitochondrial dysfunction, reducing infarct size and increasing LV contractility. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science and Technology Development Agency Thailand

Pharmacological inhibition of mitochondrial fission attenuates cardiac ischemia-reperfusion injury in pre-diabetic rats

An increase in the number of fragmented mitochondria contributes to the pathogenesis of ischemia-reperfusion (I/R) injury. Also, mitochondrial fission has shown an increase in obese condition. However, the cardioprotective roles of a mitochondrial fission inhibitor in obesity with cardiac I/R injury are unclear. We hypothesized that a fission inhibitor (Mdivi-1) reduces cardiac dysfunction during I/R injury in pre-diabetic rats. Male Wistar rats (n = 40) were received a high-fat diet for 12 weeks to induce prediabetes. Then, rats underwent a 30-min coronary artery ligation was performed followed by reperfusion for 120 min. These I/R rats were given either: (1) vehicle or Mdivi-1 treatment at 3 time points relative to onset of ischemia: (2) pre-ischemia; (3) during ischemia; and (4) at onset of reperfusion. Cardiac function, myocardial infarct size, mitochondrial function and dynamic balance were determined. Interestingly, Mdivi-1 given at any time points effectively attenuated mitochondrial reactive oxygen species production, depolarization, swelling, and dynamic imbalance, resulting in reduced arrhythmias, myocardial cell death, infarct size and enhanced cardiac performance during I/R injury in pre-diabetic rats. Taken together, inhibition of mitochondrial fission effectively protected the heart against cardiac I/R injury regardless of the time of administration in pre-diabetic rats.

Neurotensin receptor 1 agonist provides neuroprotection in pre-diabetic rats.

Exogenous treatment of a neurotensin receptor 1 (NTR1) agonist exerted the neuroprotection in an obese and Alzheimer's model. However, the effects of NTR1 modulation on peripheral/hippocampal impairment and cognitive deficit following sustained HFD consumption are poorly understood. Forty rats received a normal diet (ND) or HFD for 16 weeks. At week 13, the ND group received a vehicle (n = 8). Thirty-two HFD-fed group were randomized into four subgroups (n = 8/subgroup) with a vehicle, 1 mg/kg of NTR1 agonist, 1 mg/kg of NTR antagonist, and combined treatment (NTR1 agonist-NTR antagonist) for 2 weeks, s.c. injection. Then, the cognitive tests and peripheral/hippocampal parameters were determined. Our findings demonstrated that NTR1 activator reversed obesity and attenuated metabolic impairment in pre-diabetic rats. It also alleviated hippocampal pathologies and synaptic dysplasticity, leading to deceleration or prevention of cognitive impairment progression. Therefore, NTR1 activation would be a possible novel therapy to decelerate or prevent progression of neuropathology and cognitive impairment in the pre-diabetes.

Metabolic cardio- and reno-protective effects of empagliflozin in a prediabetic rat model.

The mechanisms behind the cardiovascular and renal benefits of empagliflozin is not fully understood. The positive impact of the medication on cardiovascular mortality can not be solely attributed to its antidiabetic effect, with a metabolic mechanism possibly involved. To investigate the metabolic effects of empagliflozin treatment (10 mg/kg/day for 6 weeks), we used an adult male rat model with serious vascular complications associated with metabolic syndrome and prediabetes. Impaired glucose tolerance, severe albuminuria and impaired insulin sensitivity were induced by intragastric administration of methylglyoxal and high sucrose diet feeding for four months. Although empagliflozin decreased body weight, non-fasting glucose and insulin, glucagon levels remained unchanged. In addition, empagliflozin increased adiponectin levels (+40%; p < 0.01) and improved skeletal muscle insulin sensitivity. Increased non-esterified fatty acids (NEFA) in empagliflozin-treated rats is understood to generate ketone bodies. Empagliflozin increased β-hydroxybutyrate levels in serum (+66%; p < 0.05) and the myocardium (30%; p < 0.01), suggesting its possible involvement as an alternative substrate for metabolism. Empagliflozin switched substrate utilisation in the myocardium, diverting glucose oxidation to fatty acid oxidation. Representing another favorable effect, empagliflozin also contributed to decreased uric acid plasma levels (-19%; p < 0.05). In the kidney cortex, empagliflozin improved oxidative and dicarbonyl stress parameters and increased gene expression of β-hydroxybutyrate dehydrogenase, an enzyme involved in ketone body utilisation. In addition, empagliflozin decreased microalbuminuria (-27%; p < 0.01) and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion (-29%; p < 0.01). Our results reveal the important systemic metabolic effect of empagliflozin on alterations in substrate utilisation and on increased ketone body use in prediabetic rats. Improved oxidative and dicarbonyl stress and decreased uric acid are also possibly involved in the cardio- and reno-protective effects of empagliflozin.

The effects of high-fat diet and metformin on urinary metabolites in diabetes and prediabetes rat models.

High-fat diet (HFD) interferes with the dietary plan of patients with type 2 diabetes mellitus (T2DM). However, many diabetes patients consume food with higher fat content for a better taste bud experience. In this study, we examined the effect of HFD on rats at the early onset of diabetes and prediabetes by supplementing their feed with palm olein oil to provide a fat content representing 39% of total calorie intake. Urinary profile generated from liquid chromatography-mass spectrometry analysis was used to construct the orthogonal partial least squares discriminant analysis (OPLS-DA) score plots. The data provide insights into the physiological state of an organism. Healthy rats fed with normal chow (NC) and HFD cannot be distinguished by their urinary metabolite profiles, whereas diabetic and prediabetic rats showed a clear separation in OPLS-DA profile between the two diets, indicating a change in their physiological state. Metformin treatment altered the metabolomics profiles of diabetic rats and lowered their blood sugar levels. For prediabetic rats, metformin treatment on both NC- and HFD-fed rats not only reduced their blood sugar levels to normal but also altered the urinary metabolite profile to be more like healthy rats. The use of metformin is therefore beneficial at the prediabetes stage.

Adverse Effects of Methylglyoxal on Transcriptome and Metabolic Changes in Visceral Adipose Tissue in a Prediabetic Rat Model.

Excessive methylglyoxal (MG) production contributes to metabolic and vascular changes by increasing inflammatory processes, disturbing regulatory mechanisms and exacerbating tissue dysfunction. MG accumulation in adipocytes leads to structural and functional changes. We used transcriptome analysis to investigate the effect of MG on metabolic changes in the visceral adipose tissue of hereditary hypetriglyceridaemic rats, a non-obese model of metabolic syndrome. Compared to controls, 4-week intragastric MG administration impaired glucose tolerance (p < 0.05) and increased glycaemia (p < 0.01) and serum levels of MCP-1 and TNFα (p < 0.05), but had no effect on serum adiponectin or leptin. Adipose tissue insulin sensitivity and lipolysis were impaired (p < 0.05) in MG-treated rats. In addition, MG reduced the expression of transcription factor Nrf2 (p < 0.01), which controls antioxidant and lipogenic genes. Increased expression of Mcp-1 and TNFα (p < 0.05) together with activation of the SAPK/JNK signaling pathway can promote chronic inflammation in adipose tissue. Transcriptome network analysis revealed the over-representation of genes involved in insulin signaling (Irs1, Igf2, Ide), lipid metabolism (Nr1d1, Lpin1, Lrpap1) and angiogenesis (Dusp10, Tp53inp1).

Worsening baroreflex sensitivity on progression to type 2 diabetes: localized vs. systemic inflammation and role of antidiabetic therapy.

Cardiac autonomic neuropathy (CAN) is an early cardiovascular manifestation of type 2 diabetes (T2D) that constitutes an independent risk factor for cardiovascular mortality and morbidity. Nevertheless, its underlying pathophysiology remains poorly understood. We recently showed that localized perivascular adipose tissue (PVAT) inflammation underlies the incidence of parasympathetic CAN in prediabetes. Here, we extend our investigation to provide a mechanistic framework for the evolution of autonomic impairment as the metabolic insult worsens. Early metabolic dysfunction was induced in rats fed a mild hypercaloric diet. Two low-dose streptozotocin injections were used to evoke a state of late decompensated T2D. Cardiac autonomic function was assessed by invasive measurement of baroreflex sensitivity using the vasoactive method. Progression into T2D was associated with aggravation of CAN to include both sympathetic and parasympathetic arms. Unlike prediabetic rats, T2D rats showed markers of brainstem neuronal injury and inflammation as well as increased serum levels of IL-1β. Experiments on PC12 cells differentiated into sympathetic-like neurons demonstrated that brainstem injury observed in T2D rats resulted from exposure to possible proinflammatory mediators in rat serum rather than a direct effect of the altered metabolic profile. CAN and the associated cardiovascular damage in T2D only responded to combined treatment with insulin to manage hyperglycemia in addition to a nonhypoglycemic dose of metformin or pioglitazone providing an anti-inflammatory effect, coincident with the effect of these combinations on serum IL-1β. Our present results indicate that CAN worsening upon progression to T2D involves brainstem inflammatory changes likely triggered by systemic inflammation.

Evidence of Altered Peripheral Nerve Function in a Rodent Model of Diet-Induced Prediabetes.

Peripheral neuropathy (PN) is a debilitating complication of diabetes that affects >50% of patients. Recent evidence suggests that obesity and metabolic disease, which often precede diabetes diagnosis, may influence PN onset and severity. We examined this in a translationally relevant model of prediabetes induced by a cafeteria (CAF) diet in Sprague–Dawley rats (n = 15 CAF versus n = 15 control). Neuropathy phenotyping included nerve conduction, tactile sensitivity, intraepidermal nerve fiber density (IENFD) and nerve excitability testing, an in vivo measure of ion channel function and membrane potential. Metabolic phenotyping included body composition, blood glucose and lipids, plasma hormones and inflammatory cytokines. After 13 weeks diet, CAF-fed rats demonstrated prediabetes with significantly elevated fasting blood glucose, insulin and impaired glucose tolerance as well as obesity and dyslipidemia. Nerve conduction, tactile sensitivity and IENFD did not differ; however, superexcitability was significantly increased in CAF-fed rats. Mathematical modeling demonstrated this was consistent with a reduction in sodium–potassium pump current. Moreover, superexcitability correlated positively with insulin resistance and adiposity, and negatively with fasting high-density lipoprotein cholesterol. In conclusion, prediabetic rats over-consuming processed, palatable foods demonstrated altered nerve function that preceded overt PN. This work provides a relevant model for pathophysiological investigation of diabetic complications.

Alteration of Intestinal Microbiota in 3-Deoxyglucosone-Induced Prediabetic Rats.

Our previous research suggests that 3-deoxyglucosone (3DG), formed in the caramelization course and Maillard reactions in food, is an independent factor for the development of prediabetes. Since the relationship between type 2 diabetes (T2D) and intestinal microbiota is moving from correlation to causality, we investigated the alterations in the composition and function of the intestinal microbiota in 3DG-induced prediabetic rats. Rats were given 50 mg/kg 3DG by intragastric administration for two weeks. Microbial profiling in faeces samples was determined through the 16S rRNA gene sequence. The glucagon-like peptide 2 (GLP-2) and lipopolysaccharide (LPS) levels in plasma and intestinal tissues were measured by ELISA and Limulus test, respectively. 3DG treatment did not significantly change the richness and evenness but affected the composition of intestinal microbiota. At the phylum level, 3DG treatment increased the abundance of nondominant bacteria Proteobacteria but did not cause the change of the dominant bacteria. Meanwhile, the abundance of the Prevotellaceae family and Parasutterela genus and the Alcaligencaeae family and Burkholderiales order and its attachment to the Betaproteobacteria class were overrepresented in the 3DG group. The bacteria of Candidatus Soleaferrea genus, Gelria genus, and Thermoanaerobacteraceae family and its attachment to Thermoanaerobacterales order were apparently more abundant in the control group. In addition, 45 KEGG pathways were altered after two-week intragastric administration of 3DG. Among these KEGG pathways, 13 KEGG pathways were involved in host metabolic function related to amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, and metabolism of terpenoids and polyketides. Moreover, the increased LPS levels and the decreased GLP-2 concentration in plasma and intestinal tissues were observed in 3DG-treated rats, together with the impaired fasting glucose and oral glucose tolerance. The alterations in composition and function of the intestinal microbiota were observed in 3DG-treated rats, which provides a possible mechanism linking exogenous 3DG intake to the development of prediabetes.

Weight Gain and Adipose Tissue Accumulation in Diabetic and Prediabetic Rats Fed with Palm Olein enriched High Fat Diet

Diabetic is known to be the main non-commutable public health concern. In this study, we evaluated the relationship between diet, body weight and accumulation of adipose tissue in healthy, diabetic and prediabetic rats. Physiologically, adipose tissue plays a central role in lipid and glucose metabolisms. Therefore, accumulation of adipose tissue in diabetic and prediabetic may lead to others non-commutable diseases. The rats in control, diabetic and prediabetic groups were fed with normal and high fat diets for 6 consecutive weeks, while the rats in 4 sub-groups of diabetic and prediabetic groups also received metformin, a common drug to control diabetes. The results indicated that in diabetic rats, a small increase of food calories by high fat diet caused a significant gained in body weight and a significant increase in adipose tissue accumulation with or without metformin treatment, however in prediabetic rats, rats with metformin treatment shown to be beneficial in maintaining body weight and adipose accumulation. The data of the study imply that balance diet at high calories should be practiced by patients as high fat diet with similar calories can caused a significant health deterioration to the patients in term of body weight gained and adipose tissue accumulation.

Potential Ameliorative Effects of Chromium Supplementation on Glucose Metabolism, Obesity, and Genomic Stability in Prediabetic Rat Model.

Chromium (III) (Cr(III)) effect on improving glucose, body mass loss, and genomic stability has been extensively studied in models of type 2 diabetes. However, there is a lack of studies evaluating its effect on prediabetes. Thus, this study evaluates the effects of Cr(III) as dietetic supplementation on glucose metabolism, obesity, and genomic stability on prediabetic rat model using high-invert sugar. Male Wistar rats were divided randomly into four treatment groups: (1) control, receiving standard diet (control); (2) prediabetic (PD), receiving a 32% of invert sugar; (3) Cr(III), receiving chromium (III) chloride (CrCl3•6H2O) (58.4mg/L); and (4) Cr(III) + PD, receiving CrCl3•6H2O in combination with high-invert sugar. Cr(III) supplementation significantly reduced blood glucose (123.00 ± 8.29mg/dL vs. 115.30 ± 9.31mg/dL, p = 0.015) and partially reduced area under the 120-min blood glucose response curve (AUC) in PD rats (p = 0.227). Moreover, Cr(III) attenuated weight gain (187.29 ± 38.56g vs. 167.22 ± 29.30g, p = 0.004), significantly reducing body mass index (0.68 ± 0.04g/cm2 vs. 0.63 ± 0.04g/cm2, p < 0.001), Lee index (0.30 ± 0.01 vs. 0.28 ± 0.01, p < 0.001), and peritoneal fat (p < 0.001). Regarding genomic stability, high-invert sugar, Cr(III), or the combination of both did not produce changes in oxidative stress, DNA damage in pancreas, or cytotoxicity markers. These data suggest that Cr(III) supplementation improved partially glucose metabolism and reduced obesity in rat model PD due to high-invert sugar without influence in genomic stability.

Amelioration of risk factors associated with diabetic nephropathy in diet-induced pre-diabetic rats by an uracil-derived diimine ruthenium(II) compound

Diabetic renal injury advances through different stages of structural and functional changes in the glomerulus, therefore treatment during the pre-diabetic state could be used as therapeutic target in the management and prevention of diabetic nephropathy (DN). Once diagnosed, dietary interventions and pharmacological therapy have been recommended to manage DN and pre-diabetic related complications. However, poor patient compliance still results, therefore newer alternative drugs are required. High fat high carbohydrates (HFHC) diet was used to induce pre-diabetes for 20 weeks. After the induction, pre-diabetic rats were randomly allocated to respective treatment groups. Subcutaneous ruthenium(II) Schiff base complex injection (15 mg/kg) was administered to pre-diabetic rats in both the presence and absence of dietary intervention once a day every third day for 12 weeks. The administration of ruthenium(II) complex resulted in reduced blood glucose, aldosterone, fluid intake and urinary output which correlated with a restoration in plasma and urinary electrolytes along with plasma antioxidants concentration. Furthermore, there was a decrease in kidney injury molecule-1 (KIM-1) concentration, albumin excretion rate (AER) albumin creatinine ratio (ACR) and mRNA expression of podocin in urine in ruthenium-treated pre-diabetic rats. Ruthenium(II) Schiff base complex ameliorated renal function while preventing the progression of DN in prediabetic-treated rats.