Fructose and Translocation of Glucokinase

Fructose can stimulate the translocation of glucokinase out of the hepatocyte nucleus. This translocated glucokinase is responsible for phosporylation of glucose. Glucose phosphorylation by glucokinase is a rate-determining step for hepatic glucose metabolism.

Under basal conditions, hepatic glucokinase is localized within the nucleus, where it is bound to the glucokinase regulatory protein (GKRP) only when glucokinase is released from GKRP can it translocate to the cytosol to allow phosphorylation of glucose. Therefore, Fructose plays a key role in helping of this translocation of Glucokinase from the nucleus to the cytoplasm.

This takes place when the regulatory protein that binds to Glucokinase bind itself instead to fructose -1-P, generated from Fructose, thereby dissociating glucokinase which now become fully active readily and fully phoshorylate incoming glucose.
 
As a result of this translocation of Glucokinase, aided by Fructose, three important effects of Fructose are seen in Diabetic Patients:

1) Improved Oral Glucose Tolerance in Adults with Type 2 Diabetes
2) Stimulating effects on Insulin-Stimulated Hepatic Glycogen Synthesis
3) Improved Ability of Hyperglycemia Per Se to Regulate Glucose

Productions Type 2 Diabetes

Details of the Research Studies proving the above three statements are given below.
 
1) Acute Fructose Administration Improves oral Glucose Tolerance in Adults with Type 2 Diabetes

In normal adults, a small (catalytic) does of fructose administered with glucose decreases the glycemic response to a glucose load, especially in those with the poorest glucose tolerance. we hypothesized that an acute catalytic dose of fructose would also improve glucose tolerance in individuals with type I1 diabetes.

RESEARCH DESIGN AND METHODS -Five adults with type 2 diabetes underwent an oral glucose tolerance test (OGTT) on two separate occasions, at least 1 week apart. Each OGTT consisted of 75g glucose with or without the addition of 7.5g fructose (OGTT + F or OFTT -F), in random order. Arterialized blood samples were collected from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 3 h afterward.
 
RESULTS
Glucose response
 
The AUC of the plasma glucose response during OGTT + Fwas 14% less than that evident during the OGTT-F(P<O.O5) the plasma glucose response was reduced by fructose in all subject, although the reeducation was very modest (~3%) in one subject . There was no significant effect of order of study on the glycemic response (P<0.3). Moreover, there was no relationship between the pre-study HbAIC, concentration and the degree of improvement in the glucose AUC between the two OGTTs(r=-0.09, P = 0.88).

NEFA, glycerol, and triglycerides
 
Plasma NEFA, blood glycerol, and plasma triglyceride concentration did not differ at any time between the two studies. NEFA concentrations declined 65-70% in relation to basal values during both OGTTs, and glycerol concentrations declined 35-45%. Triglyceride concentrations did not change significantly during either OGTT.
Thus, it is likely that fructose ingestion resulted in-improved glucose tolerance via the stimulation of net hepatic-glucose uptake secondary to enhanced translocation of glucokinase.

2. Stimulating Effects of Low-Dose Fructose on insulin - Stimulated Hepatic Glycogen Synthesis in Humans

RESEARCH DESIGN AND METHODS - Six healthy overnight-fasted subject. were infused for 4h with somatostatin (0.lug . Kgn-¹ min-¹) and insulin (240 pmol m-² min-¹). During the initial 120 min,[1-¹³ C] glucose was infused to assess glycogen synthase flux followed by an ~120-min infusion of unlabeled glucose to assess rates of glycogen phosphorylase flux. Acetaminophen was given to assess the percent contribution of the direct and indirect (gluconeogenic) pathways of glycogen synthesis by the ¹³ C enrichment of plasma UDP - glucuronide and C-1 of glucose.
 
CONCLUSIONS
 
In summary these are the first studies to demonstrate directly that small amounts of fructose can have a profound impact on stimulating net hepatic glycogen synthesis in humans. Furthermore, these studies revel
that the mechanism by which this occurs is through stimulation of glycogen synthase flux by 2.5 fold, with no significant effect to inhibit glycogen synthesis has been shown to be diminished in patients with poorly controlled Type 1 and Type I1 diabetes, stimulation of net hepatic glycogen synthesis by this mechanism may be of potential therapeutic value.

3. Fructose Improves the Ability of Hyperglycemia Per Se to Regulate Glucose Production in Type 2 Diabetes
 
RESEARCH DESIGN AND METHODS - A total of 10 subject with moderately controlled type 2 diabetes and 7 age and BMI matched non diabetic subject were studied on up three separate occasion under following conditions : without fructose (F) or with infusion of fructose at two dosages: 0.6 mg/kg min (low F) and 1.8 mg/kg. Min (high F)

CONCLUSIONS
 
Thus the administration of small amount of fructose to type 2 diabetic subjects partially corrected the regulation of GP by hyperglycemia per se, yet did not after this regulation in the nondiabetic subjects.

Consistent with the important interrelationship between GK translocation and activation of glycogen synthase, fructose acutely increases rates of glycogen synthesis in vitro in hepatocytes and in vivo in normal dogs and humans. Because the liver's ability to store glucose as glycogen is decreased in type 2 diabetes, this effect of fructose is likely to be of additional therapeutic benefit. Furthermore fructose administration increases rates of hepatic glycolysis, resulting in increased lactate production.

In summary the infusion of relatively small amounts of fructose in moderately controlled type I1 diabetic subject partially corrected the regulation of GP by hyperglycemia per se. This suggests that an impaired ability of glucose to stimulate flux through GK ultimately contributes to increased Gp in individuals with type 2 diabetes. Thus, activating the translocation of hepatic GK offers an attractive the treatment option to restore glucose induced regulation of hepatic glucose fluxes. Given the beneficial effects of Gk over expression in an insulin deficient, streptozotocin-induced mouse model of diabetes and the fact that defective regulation of hepatic glucose fluxes in diabetes is determined by the degree of chronic hyperglycemia, administration of fructose might be expected to favorably affect hepatic glucose metabolism in type 1 diabetes as well.

Reference
 
Mary Courtney Moore, PHDI, Stephen N. Davis, MD1,2,3, Stephnie L. Mann, BSNZ AND Alan D. Cherrington, PHD1,2,3, : Acute Fructose Administration Improves Oral Glucose Tolerance in Adults With Type 2 Diabetes : Diabetes Care 24: copy right American Diabetes Association, inc. Kitt Falk Petersenl, Didier Laurentl, Chunil yu2, Gary W. Clinel, and Gerald I. Shulmanl,2,3, Stimulating Effects of Low-Dose Fructose on Insulin-Stimulated Hepatic Glycogen Synthesis in Humans: Diabetes 50:1263-1268, : copy right American Diabetes Association,lnc. Meredith Hawkins, lian Gabriely, Robert Wozniak, Cristian Vilcu, Harry Shamoon, and Luciano Rosetti : Fructose Improves the Ability of Hyperglycemia Per Se to Regulate Glucose Production in Type 2 Diabetes : Diabetes 51:606-614,c 2002 by the American Diabetes Association, Inc.


Crystalline Fructose combined with a High-fiber Low fat diet appears to be safe and Acceptable for diabetic individuals when total calorie intake is controlled
 

 
The long-term was studied and evaluated in 14 middle-aged men with diabetes. Subjects followed an ambulatory high-fiber high-carbohydrate control diet at home for 8 wk, entered the hospital for 5 days on this diet and spent the next 7 days on similar diet supplemented with 50-60g fructose. They continued the fructose diet at home for 23 wk, than resumed a postcontro diet for an additional 16 wk.


In the hospital, glycemic control improved significantly on the fructose- supplemented diet compared with the hospital control diet. In the ambulatory setting, no significant differences in plasma glucose, glycohemoglobin, serum cholesterol, triglycerides, lactate or urate occurred between precontrol, fructose, or postcontrol periods. Fasting serum lactate was higher by 0.5 meq/1 during the precontrol period. Body weight also increased during the ambulatory fructose period due to higher calorie intake. Adherence to fructose consumption was excellent and improved adherence to carbohydrate and fat recommendations. Therefore, if the total calorie intake is controlled to promote fructose used with a high-carbohydrate high-fiber low-fat diet appears to be safe and acceptable for diabetic individuals.

Reference
 
JW Anderson, LJ Story, NCZettwoch, NJ Gustafson and BS Jefferson, Metabolic Research Group, Veterans Administration Medical Center: Metabolic Effects Supplementation in Diabetic Individuals : Diabetes Care, Vol 12, Issue 5 337-344, Copyright © 1989 by American Diabetes Association.