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HIGH CARBOHYDRATE - HIGH FIBER DIET

© 20 lean, type II diabetics; FBS ³ 200 despite insulin

·       Standard 43% carbohydrate diet for 7 days

·       Experimental 79% carbohydrate for 16 days

MODERATE CARBOHYDRATE  RESTRICTION

©   28 Type II diabetics

¨   All on 60% carbohydrate, 20% protein, 30% fat diet

¨   19 on sulfonylurea drugs

¨   None achieving adequate sugar control

¨   All with documented insulin resistance

·       Eight weeks of moderate carbohydrate restriction

    ¨ Calories based on ideal body weight

    ¨ Alcohol eliminated

¨   25% carbs; 85% complex and 15% simple

¨ 45% protein

¨ 30% fat

·       Taper out sulfonylureas while on the experimental diet

·       Then switch to the ADA diet for 12 weeks

 THE GLYCEMIC INDEX

·      Developed by Dr. David Jenkins in 1981

·      Rise in glucose & insulin following intake of a food

·      100 - rise after ingestion of glucose

 PLANT FIBER & BLOOD SUGAR  CONTROL

Fiber:  The portion of plants that is composed of complex

            carbohydrate polymers of simple sugars

·       Soluble

¨ Gel-forming substances, such as pectin, gum, & mucilage

¨ Efficiently degraded by intestinal bacteria

¨ Promote metabolic health

¨ Beans, legumes, oat bran, nuts, apples, pears,

    psyllium seed husks, and most vegetables

 ·       Insoluble

¨ Structural plant fibers that pass through the GI tract             unchanged, such as lignin, cellulose, and hemicellulose

¨Promote intestinal health

Properties of Soluble Fiber:

·  Decreases gastric emptying rate

        ¨ decreases appetite

        ¨ delay glucose absorption

·       Binds to and wastes dietary fat

·  Binds to and wastes bile acids

PSYLLIUM FIBER & BLOOD SUGAR CONTROL

·       Soluble fiber should help with sugar & lipid control

·       Metamucil- 5 grams of Plantago psyllium soluble fiber

                 Will Metamucil help our diabetic patients?

©   125 middle aged type II diabetic patients 

·       92% on insulin, 8% on sulfonylurea                                                            

·  Standard diet for six weeks: 50%carbohydrate                                                300 calories of protein                                                                 rest polyunsaturated fats 

·       Metamucil or placebo t.i.d. before meals ´ 6 weeks

·       Then crossover to the other treatment

·       Diet and drug therapy maintained

·       Randomized, double blind protocol

© Well tolerated - compliance excellent

        · 93% psyllium & 96% placebo doses taken

· Only 2/62 psyllium patients dropped out

      © Psyllium effects on Fasting Blood Sugar & LIPIDS

FENUGREEK

·    Trigonella fenum-graecum, common spice used in cooking

·    White flowered plant, member of the Pea family

·    Originated in Northern Africa

·    Historically used to treat DM, fevers, and indigestion

·    Found in King Tut’s tomb

           Defatted fenugreek seeds contain  

          ·      Water soluble fiber, galactomannans  

          ·       Steroidal saponins

        ¨   increase and/or enhance insulin receptors

        ¨   increase bile acid metabolism

Will fenugreek help with blood sugar control?  

FENUGREEK

©   In type I diabetics  

        ¨ 50 gm b.i.d. in flatbread ® ¯ gluc, chol, LDL, & trigs  

©   In type II diabetics  

¨   25 gm/day ® ¯ FBS and diabetic symptoms

¨   15 gm blunted post-meal rise in glucose level

¨   12.5 gm in soup b.i.d. ® ¯ LDL & trigs - HDL ­ed  

IRON REMOVAL REMOVES DIABETES  

·       Iron excess is associated with coronary heart disease  

·       Excess iron may also  

§    Compromise peripheral glucose utilization

§    Damage the pancreatic b cells  

·       Heart Disease and DM occur in Hemochromatosis  

·       The DM of Hemochromatosis responds to phlebotomy  

·       5% diabetics have high ferritins > 400(m) > 300(w)

Will DM respond to iron removal?

© Measure Ferritin levels in 18 DM II patients  

§    9 within normal range of 21-330 mg/L

§    9 with elevated values  

· 10 mg/kg IV Desferroxamine twice a week  

        ¨ until Ferritin normalizes - 16 tnts over 8 weeks

        ¨ 12 tnts over 6 weeks in control group  

Results

Conclusions - Iron in Diabetes

1. Iron overload plays a role in type II Diabetes  

2. Iron overload is relatively common in diabetics  

2. Iron chelation is safe  

3. Iron chelation in iron overloaded diabetic patients

 ELEOTIN HERBAL TEA  

· Over 2000 herbs can lower sugar levels  

       ¨ Some are toxic

       ¨ Single mechanism of action    

· In developing Eleotin  

       ¨ Looked at multiple plants

       ¨ Utilized various combinations

       ¨ Tested extensively for toxicity  

                                                      Eleotin

     Platycodi Radix            Schizandrae Fructus

     Capsella Bursa              Astragalus Membranaceus

     Nycium Chinese            Dioscorea Japonica

                 Acanthopanaz Sessiliflorum  

· Test in animals and humans  

© Study in animals - GK diabetic rat

·      Maturity onset diabetes

·      Insulin resistance

·      Impaired insulin secretion

·      Model for adult onset DM II      

       © Insulin binding in liver

  © Insulin binding in muscle 

© Glucosidase inhibitor - delays carb absorption

© Increases pancreatic insulin secretion

© Eleotin vs. Placebo in diabetic GK rats

Prevention of diabetes in GK rats

· Begin Eleotin or placebo at 3 weeks of age  

· Follow sugar values  

© Glucose lowering effects of Eleotin in humans

© Glucose levels after stopping Eleotin

©  Factors predicting efficacy  

· Shorter duration of diabetes 

· Younger patient age 

· Abstinence from alcohol 

© Guidelines for use 

B VITAMINS VS NEUROPATHY

  B vitamins are critical to:  

        ¨ Peripheral nerve structure and function

        ¨ Production of serotonin and GABA in the brain

        ¨ Perception of pain by the brain

Water soluble B vitamins are poorly absorbed, 4-6%

Benfotiamine, a fat soluble Thiamine derivative

¨   Much better absorption

¨   Higher blood and tissue levels  

Could a Benfotiamine based oral B vitamin improve nerve function   in humans with diabetic neuropathy?  

©   24 middle age diabetic patients with stable neuropathy  

     ·       Benfotiamine 90 mg, B₆ 90mg, B₁₂ 250 mcg or placebo

             ¨ Two q.i.d. ´ 14 days in hospital, then

             ¨ One  t.i.d. ´ 10 weeks at home

     ·       At baseline, 2 weeks, and 10 weeks, measure

             ¨ Nerve vibration threshold

       ¨ Nerve conduction velocity

       ¨ Lab studies

© Tolerance excellent - no side effects or change in labs

LIPOIC ACID  

·       Blood flow to the peripheral nervous system is compromised by oxidative stress  

·       Oxidative stress produces motor and sensory peripheral nerve dysfunction in diabetics     

·       Antioxidants protect against neuropathy in experimental diabetes  fat soluble antioxidants work best  

·       Lipoic acid is a fat & water-soluble antioxidant

·       Lipoic acid encourages regeneration of damaged nerves

Could Lipoic acid, a potent, fat soluble antioxidant, improve nerve function and reduce diabetic neuropathy symptoms in humans?

©  The ALADIN Study

Alpha Lipoic Acid in Diabetic Neuropathy

·       260 type II diabetics with symptomatic neuropathy

·       None on antioxidants, B vitamins, or EFAs

·       Usual diet and medication

·       22 IV treatments over five weeks

                     ¨ 1200 mg LA          ¨  600 mg LA

             ¨   100 mg LA          ¨     Placebo

· Randomized, double blind, multicenter protocol

        CAYENNE PEPPER VS. NEUROPATHY

·  Capsacin is the pungent principle of Cayenne spp.

·  Depletes substance P and numbs sensory nerves

®Reduces the sensation of pain

®Capsacin cream helps relieve pain in post-herpetic neuralgia and post-mastectomy syndrome

Can capsacin cream reduce the pain of diabetic neuropathy?

©   277 type I and type II diabetics with painful peripheral neuropathy

·       0.075% capsacin or placebo cream q.i.d. to painful areas

·       Analgesics allowed for early treatment burning

·       All other meds held constant

·       Evaluate every 2 weeks over 8 weeks

·       Measure the presence and severity of pain 

¨   MD global evaluation:  (+3) much better ®

(0) no change ® (-2) much worse

            ¨ Patient visual analog scale of pain intensity

    ¨ Visual analog scale of pain relief     

 ·       Randomized, double blind protocol; 12 centers involved

1^st two weeks - ­ed burning due to capsacin; 9 dropped out

By 8 weeks    -  significant ¯ in pain intensity and

                          significant ­ in MD evaluation  
          

©   Patient tolerance - Moderate  

FISH OIL vs NEUROPATHY

· Proven benefits in cardiovascular disease  

· Fish oil increases the blood sugar in diabetics, 

  but fish oil with vitamin E does not  

· EFAs are involved in normal nerve function

  Þ Will fish oil relieve neuropathy symptoms in diabetic patients with concomitant vascular disease?  

©  21 diabetic patients with

¨ Painful neuropathy

¨ Vascular disease with absent foot pulses  

· 600 mg purified EPA tid with meals ´ 48 weeks

· Monitor over the course of treatment  

1. Symptoms - coldness and numbness

2. Vibratory perception threshold

3. Lab values

4. Cross sectional area of the Dorsalis Pedis artery  

  BILBERRY VS. DIABETIC RETINOPATHY

Vaccinum myrtillus, the European Blueberry  

Anthocyanidin bioflavonoids - protect and repair vascular   

                                                  wall connective tissues  

A.  Promotes glycosaminoglycan synthesis

B.  Decreases capillary permeability - less leaky

C.  Relieves  abnormal intercellular edema fluid collection

D.  Decrease basement membrane thickness  

Can Bilberry favorably effect diabetic retinopathy?

Bilberry fruit extract standardized to 25% anthocyanosides

©   40 diabetic patients, 37 with retinopathy

·       160 mg or placebo b.i.d. for four weeks

·       Double blind, crossover protocol

Of the patients with retinal abnormalities on eye exam

·       None improved on placebo

·       79% improved on bilberry

Of the patients with abnormal fluorescin angiograms

·       None improved on placebo

·       86% showed mod. to sig. improvement on bilberry

BIOTIN - NOT JUST FOR EGG SUCKERS

Available in diet and manufactured by gut microflora

Avidin, present in egg white, can inactivate biotin

Þ Biotin deficiency occurs only in egg suckers

Biotin is critical to intracellular glucose metabolism

Low biotin ® glucose metabolites build up

                       ® intracellular glucose builds up

                           ® glucose spills out into circulation

              ® diabetes mellitus

Feed egg white to rats ® biotin deficient ® diabetic

Can humans become biotin deficient?

Could biotin deficiency cause some diabetes?

Will biotin supplements help with sugar control?

©   43 middle age patients with DM II of 5 years duration

·       All on diet and glyburide

·       All with poor diabetic control

·       Average FBS 170 mg/dl

·       Abnormal glucose tolerance test

·       64 age matched healthy control subjects

¨   Average biotin level was 41% lower in the diabetics

      56.7 vs. 96.8 nmol/L in controls

 ¨ Biotin level was inversely related to the FBS

©   Hold glyburide for 4 weeks in 28 patients

·       18 randomly selected to take biotin 3 mg t.i.d.

·       10 receive placebo t.i.d.

  Can biotin help in drug resistant diabetics?

©   5 patients - no response to 1yr of glyburide 10 mg

·       Add biotin 3 mg t.i.d. to drug therapy   

        ©  FBS fell  

        © Insulin level unchanged

©   13insulin dependent diabetics

·       Measure plasma biotin levels

·       Correlate with the level of glucose control

·       Hold insulin for one week, and treat with

¨   Biotin 16 mg/day, or

¨   Placebo  

        ©  FBS and Biotin levels are inversely related

      © FBS rose on placebo

      © FBS fell from 266 to 126 on Biotin

               BIOTIN - CONCLUSIONS  

1. Biotin is necessary for intracellular glucose metabolism    

2. Biotin deficiency is common in diabetics

3. Biotin deficiency compromises sugar control

4. Drug resistance may be due to biotin deficiency

5. Supplementation enhances the response to oral therapy

6. Supplementation alone improves diabetic control

7. Biotin may also help relieve symptoms of neuropathy

GLYCOSAMINOGLYCANS  

Microalbuminuria - albumin wastage by the kidney

·      Early sign of diabetic nephropathy  

·      Predicts cardiovascular mortality

Due to microvascular disease in the kidney

·      Oxidative attack on the capillaries

·      Glycosylation of vascular wall proteins

·      Decreased production of heparan sulfate

·      Thickening of the capillary basement membrane  

©   12 middle age, hypertensive, DM II patients

    ·       Standard diet and insulin therapy maintained

    ·       Placebo controlled cross-over study

    ·       6 - sulodexide 100 mg/day ´ 4 months, then placebo

    ·       6 - placebo ´ 4 months, then sulodexide  

Microalbuminuria (mg/min)

 BP over 4 months

Plac 155/81 - 157/82

Sulo 155/81 - 144/74  

GLYCOSAMINOGLYCANS

1. Tone up the function of the vascular wall  

2. Supplementation safe and well tolerated  

3. Modest effect on blood sugar control    

4. Beneficial effect on blood pressure

5. Marked reduction in fibrinogen  

6. Reverse microalbuminuria  

CHROMIUM

·       Necessary co-factor for insulin function

·       90% Americans are chromium deficient

·       Diabetics need more chromium than do normals

·       American diabetics will be chromium deficient

·       Could chromium improve blood sugar control?

©   US-China Chromium Study - 180 DM II patients

·       Usual diet and medications were continued

·       Four month intervention

¨   60 received placebo b.i.d.

¨   60 chromium picolinate 100 mcg b.i.d.

¨   60 chromium picolinate 500 mcg b.i.d.

THE CHROMIUM - NIACIN CONNECTION

·  In animal studies, the response to chromium is uniform;

    all diabetic or chromium deficient animals improve

·  In human studies the response is non-uniform; 

    some subjects do not respond to chromium alone

·  Remember that Glucose Tolerance Factor contains

    chromium and niacin

©   Chromium plus niacin vs. chromium or niacin alone:

        Treatment                                        Response

200 mcg chromium chloride         No change in blood sugar

100 mg niacin                                No effect

Chromium + niacin                      FBS ¯ 7% from 96 to 89

                                              15% ¯ in blood sugar

                                                      rise following a meal

·  Diabetics have difficulty synthesizing GTF from

    chromium and niacin. 

·       Therefore, co-administration of niacin , 10 mg for every 100 mcg chromium, is appropriate in diabetics

  CHROMIUM vs. GESTATIONAL DIABETES

·       Chromium deficiency causes/aggravates diabetes  

·       Chromium deficiency is common in Americans  

·       Chromium supplementation improves insulin sensitivity  

·       Diabetes is common during pregnancy  

·       Mother Nature robs the mother to nourish the baby  

·       Chromium depletion occurs during pregnancy  

·       Lab breeder rats all become progressively diabetic  

Is chromium deficiency playing a role in

   human gestational diabetes?

Could supplementation help?

CHROMIUM vs. GESTATIONAL DIABETES

©   30 women with gestational diabetes  

·       20-24^th week of pregnancy

·       All with abnormal glucose-insulin tolerance tests

1. Dietary change initiated  

2. Insulin added if diet and study treatment ineffective  

3. Randomize to Chromium Picolinate or placebo

Needed insulin

¨ 4 mcg/kg, » 200 mcg                3

¨ 8 mcg/kg, » 400 mcg                1

¨ Placebo                                     4

4.  Repeat the glucose-insulin tolerance tests at 8 weeks

EFAs IN DIABETIC NEUROPATHY

·       Prostaglandins derived from GLA are important in nerve membrane structure, nerve blood flow, and nerve conduction

·       Conversion of dietary LA into GLA is defective in diabetics

·       Peripheral neuropathy is a common complication of diabetes

In diabetic animals, supplementation with GLA:

§ Restores abnormally reduced nerve blood flow;

    ­ prostacyclin ® nitric oxide Þ vasodilation

§ Corrects the nerve conduction defect present

In diabetic humans

§ Conversion of dietary fatty acids into the essential

    fatty acid precursors of the beneficial series 1 and

    3 prostaglandins is impaired  

§ Cell membrane omega-6 and omega-3 fatty acid

    levels are reduced relative to non-diabetics

©   Three studies of GLA in diabetic neuropathy - Twelve

500 mg Evening Primrose Oil capsules/day(480 mg GLA)

or placebo; randomized, double-blind format

Six physiological parameters; i.e. conduction velocity

Six clinical measures; i.e. muscle strength and reflexes

Two thermal indicators; i.e. ability to perceive temp D

Evaluate upper and lower extremities Þ 28 parameters

© GLA for six months in 22 patients - pilot study

        All parameters improved in the GLA group

        All parameters deteriorated in the placebo group

© Multicenter study of GLA; 111 patients at 7 centers x 1 yr

        25/28 parameters improved from baseline with GLA

        26/28 parameters deteriorated in the placebo group

        26/28 parameters did better with active treatment    

© 2^nd multicenter study of GLA; 293 patients at 10 centers

        23/28 parameters improved from baseline with GLA

        All 28 parameters deteriorated in the placebo group

        27/28 parameters did better with active treatment

Side-effects similar in GLA and placebo groups

 GYMNEMA SYLVESTRE

Woody vine indigenous to Southern and Central India

Gurmar in Hindi, meaning “sugar destroying”

Shustra, a 6^th centrury BC Ayurvedic, described the ability of gymnema leaf to eliminate the sweet taste of sugar 

Anti-diabetic properties 

1. Decreases glucose absorption from the intestine 

2. Enhances insulin release from Beta cells 

3. May regenerate pancreatic Beta cells 

4. Beneficial in experimental diabetes 

5. Reduces sweet taste sensation for 90 minutes 

6. Crude herb may interfere with iron absorption 

7. GS₄ standard extract used in medical applications 

Will Gymnema help with blood sugar control in humans?  

©   75 type I diabetics, age 10-50 years

·       38 received 200 mg GS4 b.i.d. and usual insulin

·       37 received their usual insulin alone 

  © Tolerance - Excellent; no side effects

©   47 middle-age type II diabetics,

·       25 receive their usual sulfonylurea

·       22 their usual sulfonylurea & GS₄ 400 mg daily

         © Tolerance - Excellent

·  No side effects

·  Sense of well being and alertness improved  

·       Meds decreased; fully discontinued in 23%

  Conclusions

In type II diabetics and type I diabetics with some residual pancreatic function, the GS₄ Gymnema sylvestre preparation will:  

1. Promote insulin release

2. Lower fasting blood sugar and HbA1c 

3. Decrease protein glycosylation 

4. Lower cholesterol and triglyceride level 

5. Decrease insulin and sulfonylurea requirements 

6. Without side effects and treatment cost is low 

   VITAMIN E

Fact:  Vitamin E is of proven value in CV disease

·       Biological oxidation initiates and aggravates vascular dz

·       We are deficient in E and other antioxidants

·       E supplementation prevents and stabilizes vascular dz 

Fact:  DM, like vascular dz, is common in the US

·       Both diseases are associated with aging

·       Oxidative stress will compromise sugar control

¨   Impairs cellular utilization of glucose

¨   Produces a state of relative insulin resistance

·  Insulin resistance is seen with “normal” aging

·       Insulin resistance is frequently seen in coronary patients

·       The leading cause of death in diabetics is vascular dz

Question:  Are oxidative stress, insulin resistance, diabetes,

                  and cardiovascular disease all intertwined?

Question:  Could Vit E be of therapeutic value in DM?

Could Vitamin E:

·       Improve blood sugar control?

·       Blunt protein glycosylation?

·       Attenuate the vascular consequences of DM?

·       Help prevent diabetes?

©  Effect of Vitamin E in diabetic and non-diabetics

· 10 healthy controls and 15 DM II patients

· Vit E 900 mg/day or placebo for 4 months

· Evaluate the effect of Vitamin E on:

¨   Vit E level           ¨  GSSG:GSH

¨   RBC viscosity     ¨  AUC on GTT

¨   Total body glucose disposal rate

¨   Glucose control parameters

· Randomized, double blind, crossover protocol

Normal Controls

Diabetic Patients

©  Vitamin E in non-diabetic coronary patients

·       30 elderly, overweight patients with angina

·       Vit E 900 mg/day or placebo for four months

·       Evaluate Vit E effects on glucose, insulin, lipids, rbc viscosity, & free radical activity

·       Randomized, double blind, crossover protocol