Oil Palm Phenolics and Diabetes: Lessons from the Nile Rat

Transcription

1 Oil Palm Phenolics and Diabetes: Lessons from the Nile Rat Julia Bolsinger, Andrzej Pronczuk, Ravigadevi Sambanthamurthi, KC Hayes Hayes Laboratory and MPOB 5/21/213

2 The Nile grass rat (Arvicanthis niloticus) Natural habitat: sub-saharan Africa Originally used in research for circadian studies But..: extremely susceptible to type 2 diabetes and metabolic syndrome when fed lab chow!

3 Chronic diabetes is associated with Handling pi cataracts and nodular hepatomas Tumor photo Cataract in old diabetic NR Hepatic tumor

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5 Objectives posed: Characterize the nature of diabetes and Metabolic Syndrome in terms of blood glucose, plasma lipoproteins, and insulin dynamics, as well as organ damage (kidney, liver, pancreas). Define the relative impact of diet composition (glycemic index and load) and dietary supplements (PFJ, lentil polyphenols) on the incidence and progression of the disease. Determine the applicability to humans by testing established antidiabetic drugs (Acarbose, Metformin, insulin)

6 Hypothesis: Pathogenetic mechanisms of type 2 diabetes in the NR Blood glucose (random, HbA1c) Insulin resistance (2) Insulin resistance (1) Absorption β-cell damage (ROS; mitochondrial DNA mutations insulin deficiency)

7 è Three main mechanisms constituting pathogenesis a) Intestinal glucose absorption b) Insulin resistance c) Insulin secretion

8 è Possible therapeutic interventions a) Alter intestinal CHO absorption

9 Body weight and random blood glucose in Nile rats after 3wks and 7wks of feeding hicho (CHO:fat:prot=7:1:2), modcho (4:4:2), or hicho+hifiber (7:1:2, cellulose) (NR St. 48) BW (g) a,b a b RBG (mg/dl) a,b a,b a,c a,c b,c b,c 3 7 Feeding time (wks) HiCHO ModCHO HiCHO+hiFiber

10 A locho diet (1:7:2) led to higher terminal body weight while maintaining normoglycemia, while hicho rats developed random hyperglycemia (NR St. 45B) p<.5 BW (g) initial 4wks 7wks hicho locho RBG (mg/dl) intial 4wks 7wks

11 Nile rats gained less weight and remained normoglycemic when Acarbose (.15mg/kcal) was added to the standard hicho diet (NR St ) 12 p< p<.5 BW (g) RBG (mg/dl) MB 73-Acarb

12 Random blood glucose and plasma lipids remained normal for Nile rats fed green lentils. Body and liver weight were reduced (NR St. ) BW (g) Initial p<.5 After 4wks After 7wks HiCHO GL RBG (mg/dl) p<.5 Initial After 4wks After 7wks p<.5 p< p< TC (mg/dl) TG (mg/dl). Liver wt (%BW)

13 Male Nile rats aged 5wks gained weight and reduced hyperglycemia after 3wks of eating the green lentil diet (NR St. 86) 25 2 p< BW initial After 3wks RBG

14 Body weight remained stable while random blood glucose decreased in diabetic male Nile rats after 2wks of feeding the green lentil diet (NR St. 76B) BW p<.5 RBG Initial After 2wks

15 Rats aged 12wks or younger gained weight and reduced blood glucose, while older rats lost weight and failed to reduce their hyperglycemia. BW (g) wks 16-64wks 6 RBG (mg/dl) p< wks 16-64wks

16 Random blood glucose remained normal for Nile rats primed with green lentils and subsequently challenged with modcho or continued on lentils, while hicho rats developed hyperglycemia (NR St. 83) 35 3 RBG (mg/dl) a,b a b initial after 4wks after 6wks after 1wks hicho modcho GL

17 b) Improvement/ prevention of insulin resistance

18 Green lentils reduced random blood glucose in diabetic Nile rats compared to hicho rats. Addition of PFJ (GAE intake 253mg/ kg BW) additionally reduced insulin levels (NR St. 97) RBG (mg/dl) a,b a,b a a b b wks 4wks 7wks HiCHO GL GL+PFJ BG (mg/dl) a a,b a b Insulin 65±45 a 58±38 b 28±15 a,b

19 PFJ (GAE intake 319mg/ kg BW) mixed into a modcho diet decreased random blood glucose in diabetic Nile rats (NR St. 4) 5 4 RBG (mg/dl) 3 2 p<.5 Initial After 2wks After 4wks After 6wks Control PFJ

20 c) Enhancement of insulin secretion

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22 Reduced insulin and blood glucose levels for the lowest OPP intake due to prevention of CHO absorption or improved insulin resistance. Increased insulin for higher OPP intakes suggests additional stimulation of insulin secretion (NR St. 11) Insulin (mu/l) a b,c c b 18 FBG (mg/dl) a,b a b

23 PFJ reduced random blood glucose when mixed into the diet (GAE intake 396mg/ kg BW) or as a drink (GAE intake 273mg/ kg BW) compared to hicho controls (NR St. 73B) 3 a,b RBG (mg/dl) 2 a b 73A drink water 73A PFJ 73A drink PFJ

24 PFJ supplementation (GAE intake 648mg/ kg BW) resulted in reduced fasting blood glucose, plasma total cholesterol and triglycerides after 36wks in chow-fed Nile rats (NR St. 7) 2 p<.5 FBG (mg/dl) 15 5 Ini9al A;er 12wks A;er 36wks Water PFJ 7 6 p<.5 Lipids (mg/dl) p<.5 TC TG

25 Summary points HiCHO causes rapid T2DM induction in young Nile rats; low CHO (high fat) and Acarbose protect, but modfat-modcho (i.e. average American diet) slowly leads to diabetes over time. Low GI foods (green lentils) protect with lasting benefit. Insulin resistance (high insulin with normal fasting glucose) develops from the initial random hyperglycemia associated with simple hicho Insulin depletion eventually results from increased stress on the beta cells

26 PFJ has antidiabetic and anti-hyperlipemic qualities likely has multiple synergistic effects is increasingly effective with higher GAE intakes is effective both as a drink or mixed into diets is effective in rats of different ages and diabetes stages did not have any observed toxic effects

27 Conclusion: Therapeutic targets to prevent/improve diabetes Insulin resistance (1) Blood glucose (random, HbA1c) Absorption Insulin resistance (2) β-cell damage (ROS; mitochondrial DNA mutations insulin deficiency)