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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

 

 

Control

Experimental

 

gm/day

% cal/day

gm/day

% cal/day

Protein

92

20 %

98

21 %

Carbohydrate

191

43 %

314

70 %

   Simple

79

 

91

 

   Complex

112

 

223

 

Fat, total

74

37 %

18

9 %

  Saturated

26

 

5

 

  Unsaturated

48

 

13

 

Cholesterol

.48

 

.065

 

Plant Fiber

26

 

65

 

  Insoluble

16

 

53

 

  Soluble

10

 

12

 

 

¨  Effect on insulin and glucose levels

 

Blood Sugar

              Insulin Dose

Fasting

3 Hour

 

Ctrl

HPF

Ctrl

HPF

Ctrl

HPF

15-20

17

0.2

165

128

142

140

22-34

30

12

178

168

209

224

40-57

48

42

180

167

-

-

Total

26

11

164

152

189

172

 

¨  Effect on lipid values

 

Cholesterol

Triglycerides

 

Control

HPF

Control

HPF

15-20

197

148

144

13

22-34

225

152

149

140

40-57

187

135

96

89

Total

206

147

131

128

 


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

       

©  Patients previously on drug therapy

 

 

Baseline

25% Carb

60% Carb

 

FBS

258

192

183

 

HbA1c

9.9

8.1

8.9

 

Weight

167

164

169

 

   

© Patients previously on diet alone

 

Baseline

25% Carb

60% Carb

 

FBS

261

172

231

 

HbA1c

9.2

7.8

9.0

 

Weight

180

178

180

 



 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

 

Food

Index

Food

Index

Sugars

 

Grains

 

Glucose

100

Puffed rice

95

Maltose

105

Cornflakes

80

Honey

75

Whole gr brd

72

Sucrose

69

Rice

70

Fructose

20

White bread

69

Fruits

 

Wheat cereal

67

Raisins

64

Corn

59

Bananas

62

Bran cereal

51

Orange juice

46

Oatmeal

49

Oranges

40

Pasta

45

Apples

39

Legumes

 

Vegetables

 

Peas

39

Potato, baked

98

Beans

31

Potato, boiled

70

Lentils

29

Beets

64

Misc.

 

Carrot, cooked

36

Ice cream

36

Carrot, raw

31

Milk

34

 

 

Sausage

28

 

 

Nuts

13

 

 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

 

Placebo

Psyllium

Wk 0

198

194

Wk 6

180

175

Wk 12

187

140

% D

+ 4%

- 20%

  

 

Placebo

Psyllium

 

Wk 0

Wk 12

% D

Wk 0

Wk 12

% D

Chol

232

215

- 7%

221

195

- 12%

LDL

157

140

- 11%

146

118

- 20%

Trigs

200

184

- 8%

186

137

- 26%

HDL

32

35

+9%

35

51

+46%


 


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

 

 

Ferritin

Glucose

HbA1c

Chol

Trigs

 

Pre

Post

Pre

Post

Pre

Post

Pre

Post

Pre

Post

Controls

197

141

317

301

8.6

8.5

211

200

201

208

­ Ferritin

595

275

258

150

8.2

5.8

262

218

414

215

nl range

2-330

68-131

4.0-6.0

120-250

34-142

   

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

    improves sugar and lipid control 

   


 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

 

Tnt

Placebo

Eleotin

Mos.

Glucose

% diabetic

Glucose

% diabetic

0

381

90

387

90

1

390

90

334

80

2

403

90

271

70

3

387

95

251

60

4

393

95

231

50

5

395

95

201

35

6

389

95

175

25

7

394

95

146

15

 

 

 

 

 

 



Prevention of diabetes in GK rats

 

· Begin Eleotin or placebo at 3 weeks of age  

· Follow sugar values  

Age in

Placebo

Eleotin

weeks

Glucose

% diabetic

Glucose

% diabetic

         

3

145

0 %

147

0 %

5

168

0 %

156

0 %

7

211

25 %

165

5 %

10

354

70 %

168

10 %

   

 

                   

 

 

 


© Glucose lowering effects of Eleotin in humans

Pat.

Duration

DM-yrs

Duration Tnt-mos

Glucose Pre

Glucose Post

Insulin Post

P.T.

15

6

469

210

Yes

H.G.

14

4

425

187

Yes

J.S.

13

8

417

132

No

T.Y.

12

7

406

162

Yes

L.H.

12

4

425

187

Yes

B.H.

11

3

380

132

No

K.T.

10

6

429

173

No

O.P.

9

6

425

168

No

Y.S.

7

6

398

180

No

K.D.

5

4

320

128

No

     

 


© Glucose levels after stopping Eleotin

 

Glucose

 

Pre-Eleotin

Post-Eleotin

3 mos out

Y.S.

398

180

183

K.T.

429

173

170

K.D.

320

128

134

O.P.

425

168

186

B.H.

380

132

134

J.S.

417

132

137

L.H.

396

178

175

Average

338

156

160

 

 

©  Factors predicting efficacy  

· Shorter duration of diabetes 

· Younger patient age 

· Abstinence from alcohol 

© Guidelines for use 

Disease severity

Effect begins

Decrease dose

Mild     < 3 yrs

1-3 mos

6 mos

Mod      < 3 yrs

3-6 mos

1-2 yrs

Severe   > 6 yrs

6-12 mos

several yrs



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

 

© Vib Percep Wrist

 

W 0

W12

% D

Plac

1.8

1.9

 + 5

B vit

2.9

1.4

- 52

 

 

 

 

 

 

 

 

© Vib Percep Ankle

 

W 0

W12

% D

Plac

11.9

15.7

+ 32

B vit

17.0

12.0

- 42

 

© Nerve Cond Vel Leg

 

W 0

W12

% D

Plac

43.1

40.4

- 6

B vit

40.2

41.3

+ 2



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

   

©  Effect on symptoms and tolerance to treatment

 

TSS

MD Rating

Adv Rxns

Tolerance

Placebo

58%

46%

21%

98%

1200 mg

71%

62%

33%

83%

600 mg

82%

76%

18%

95%

100 mg

65%

53%

14%

93%


        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

   

1st 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  

 

No.

 

Pts

Burn

 

Cough

Other

Drop

Capsacin-138

135

108

87

16

32

38

Placebo-139

49

41

23

2

24

20

   

© % Improving

 

 

 

 

 

MD scale

¯ Intensity

Pain Relief

 

Wk 2

Wk 8

Wk 2

Wk 8

Wk 2

Wk 8

Placebo

43

51

14

28

31

45

Capsacin

57

71

17

40

36

60

 


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  

        

Change in Vibratory Perception Threshold - mm

 

Before

 Fish Oil Supplementation

 

0 wks

12 wks

24 wks

48 wks

Ankle

32

19

22

16

Wrist

13

9.5

9.6

9.8

 

Change in Dorsalis Pedis Artery

 

Before

 Fish Oil Supplementation

 

0 wks

12 wks

24 wks

48 wks

 

Area(mm2)

2.5

3.4

3.3

3.9

 

Flow Index

17

25

34

46

 

 

Change in Lab Parameters

 

Before

 Fish Oil Supplementation

 

0 wks

12 wks

48 wks

% D

 

% EPA

3.0

5.5

5.7

+ 90%

 

Glucose

138

147

166

+ 20%

 

HbA1c

7.3

7.3

7.6

+ 4%

 

Trig ³ 150

263

175

214

- 19%

 

Trig < 150

85

70

82

- 4%

 

Chol ³ 220

235

210

216

- 8%

 

Chol < 220

184

178

185

no D

 

Albumin-U

24

12

14

- 42%

 



  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.

 

0 wks

4 wks

% D

Glucose

231

127

- 45%

Pyruvate

107.4

63.8

- 40%

Lactate

2.32

1.25

- 46%

 

    ©   20 with poor response to diet & drug therapy

·       Diet maintained, glyburide discontinued

·       Biotin 3 mg t.i.d. plus Clostridium butylium

·       Two to four year follow-up

 

Results

     ·       FBS normal in two months

     ·       Insulin level unchanged

     ·       Body weight unchanged

     ·       No side effects



  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

    

Can biotin help with diabetic neuropathy?

 

©   Three patients with severe neuropathy

·       Biotin 10 mg/day IM for 6 weeks, then

10 mg/day IM M, W, & F for 6 weeks, then

 5 mg/day orally for 1-2 years

 

¨     Within 4 to 8 weeks painful muscle cramps,

       tingling, and ability to walk improved;

       restless leg syndrome resolved


 

©   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  

 

 

FBS

HbA1c

Fibrinogen

 

Start

4 mos

Start

4 mos

Start

4 mos

Placebo

210

161

7.9

8.8

463

428

Sulodexide

172

125

7.6

7.2

466

247

   

Microalbuminuria (mg/min)

 

 

Baseline

4 Months

8 Months

Placebo/Sulo

120

220

44

Sulo/Placebo

135

36

44

 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.

At 4 months Placebo 200 mcg 1000 mcg Decreased by
FBS 158 135 127 20%
2 hr sugar  221 224 188 15%
HbA1c 8.5 7.5 6.6 22%

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  

·       20-24th 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

   

 

 

Placebo

4 mcg/kg

8 mcg/kg

Fasting

Glucose

87

82

79

 

Insulin

23

13

12

One hour

Glucose

186

154

145

 

Insulin

122

71

92

 


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    

 

© 2nd 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 6th 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 

 

© Effect on Insulin Release

C-Peptide

Volunteers

Insulin

GS4

 (.15-.34)

.27

.11

.19

  

© Effect on Sugar, Cholesterol, & Kidney Function

 

Insulin

FBS

HbA1c

Chol

Trig

BUN

Normal

 

-

89

6.0

179

90

24

Insulin

Base

55

233

12.7

225

124

22

 

1 yr

55

224

11.8

209

112

22

 

% D

-

- 4

- 7

- 7

- 10

-

GS4

Base

60

232

12.8

206

134

25

 

1.5yr

35

150

9.0

194

120

19

 

2 yr

25

152

8.5

176

107

18

 

% D

- 58

- 34

- 33

- 14

- 20

- 28

  © Tolerance - Excellent; no side effects


©   47 middle-age type II diabetics,

·       25 receive their usual sulfonylurea

·       22 their usual sulfonylurea & GS4 400 mg daily

 

 ©  Fasting and Post-Prandial Insulin Levels

 

Fasting

Post-Prandial

Volunteers

30

95

Usual Therapy

13

50

GS4 Group

21

63

 

 ©  FBS, Glycoprotein, & Lipid Values

 

 

FBS

GlycoPrt

Chol

Trigs

Usual

Initial

150

10.2

252

148

 

1 year

157

10.5

261

164

 

% D

+ 5%

+ 3%

+ 4%

+ 16%

GS4

Initial

174

12

260

170

 

1 year

146

9.7

242

156

 

2 year

124

8.5

231

142

 

% D

- 17%

- 30%

- 11%

- 16%

         © 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

 

Vitamin E level

GSSG:

GSH

RBC

Viscosity

AUC

GTT

TBGD

Placebo

2.5

.88

.224

344

39

Vit E

8.4

.64

.215

287

48

E vs P

+ 235%

- 21%

- 4%

- 17%

+ 23%

  

Diabetic Patients

 

Vitamin E level

GSSG:

GSH

RBC

Viscosity

TBGD

Placebo

.16

1.21

.245

19

Vit E

6.2

.65

.220

28

E vs P

+ 3000%

- 46%

- 10%

+ 47%

 

 

FBS

2 hr sugar

GTT-AUC

HbA1c

Placebo

131

248

614

7.9

Vit E

120

226

514

7.0

E vs P

- 8%

- 9%

- 16%

- 11%

 


©  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

  

 

Vitamin E

O2 Radicals

Microviscosity

Placebo

8.9

0.21

.283

Vit E

54.8

0.09

.231

E vs. P

+ 515 %

- 57 %

- 19 %

  

 

Glucose

Insulin

 

 

Fast

2 hr

% D

Fast

2 hr

% D

Placebo

102

131

+28 %

8.8

34.8

+338 %

Vit E

102

125

+22 %

6.8

26.3

+348 %

               

  

 

Chol

LDL

HDL

Trigs

LDL:HDL

Placebo

269

231

30

119

7.6

Vit E

233

191

34

95

5.5

E vs. P

- 12 %

- 17 %

+ 13 %

- 20 %

- 27 %

 


©  Vitamin E and protein glycosylation

·       Non-Enzymatic Protein Glycosylation - NEG

       ¨ Sugar + Protein + Heat = Glycosylated Protein

       ¨ Browning rxn in cooking & food processing

       ¨ Maillard reaction in chemistry

       ¨ HbA1c and glycosylated protein levels

       ¨ Predictive of diabetic complications

·       Antioxidants block the Browning reaction

·       Vitamin E blocks the Maillard reaction

·       Could E block protein glycosylation in diabetics?

 


©   30 insulin dependent diabetic adults

·       Insulin & standard diet continued in all

·       Four months of intervention

¨10 received placebo

¨  600 mg/day Vit E in 10

¨1200 mg/day Vit E in 10

·       Look for an E effect on protein glycosylation

 

 

E level

Gluc

HbA1c

GlycProt

Placebo

9.8

185

1.2

1.8

E 600 mg

21.4

190

.83

1.4

E 1200 mg

31.2

187

.48

1.2

 


       VITAMIN E AND FUTURE DIABETIC RISK

 In Finland vs. Europe

 

·      Dietary Vit E intake is low:  60% < 10 mg RDA

·      Average E level 19 mmol/L vs 26 elsewhere

·      Prevalence of DM II is higher and rising 

Could the Finn’s low Vit E status be playing a role?

 

© 1000 healthy Finnish men age 42-60  

·      Non-diabetic:  FBS < 120; 2 hr sugar < 180

·      Measure Vit E level and other parameters

·      Evaluate for DM II four years later

 

Risk Factor for DM II

Rel. Risk

No increased risk

   1.0

Smoking

   1.015

Age

   1.02

Socioeconomic status

   1.1

High Sat:Unsat fat ratio

   1.1

Body mass index

   1.23

Below median Vit E

   3.9

 

5% decrease in Vit E Þ 22% increase in risk


VITAMIN E - CONCLUSIONS

 

VITAMIN E in DM, INSULIN RESISTANCE, & CADz

 

©   Healthy, non-diabetic adults without coronary disease

·       Reduces oxidative stress

·       Enhances cellular glucose utilization

·       Attenuates insulin resistance

·       Protects against diabetes

 

©   Non-diabetic adults with coronary disease

·       Reduces oxidative stress

·       Enhances cellular glucose utilization

·       Attenuates insulin resistance

·       ¯es Chol, LDL, Trigs and ­es HDL

 

©   Diabetic patients

·       Are relatively deficient in Vitamin E

·       Experience greater oxidative stress

·       Supplemental E will:

 

¨   Resolve the oxidative stress 

¨   Improve cell membrane viscosity and function 

¨   Reduce insulin resistance, enhance cellular glucose uptake, and improve diabetic control 

¨   Blunt abnormal protein glycosylation


VITAMIN C

 

            GLUCOSE                       VITAMIN C 

 

         H ¾ C = O                         O ¾ C ¾¾

                  ½                                            ½   

         H ¾ C ¾ OH                 OH ¾ C  

                  ½                                            ½        O

      HO ¾ C ¾                   OH ¾ C        

                  ½                                             ½

         H ¾ C ¾ OH                    H ¾ C ¾¾

                  ½                                            ½

         H ¾ C ¾ OH                HO ¾ C

                  ½                                            ½          

                  CH2OH                              CH2OH

                 


·      Functions of Vitamin C: 

    ¨ Formation of collagen   ¨ Antioxidant

    ¨ Protein synthesis           ¨ Immune system 

· Vitamin C and glucose are structurally similar 

· Insulin facilitates the transfer of vitamin C into cells 

    Þ Diabetics are C & intracellular C deficient

 

 

Intake

Vit C level

Controls

70 mg

68 mmol/L

Diabetics

61 mg

30 mmol/L

 

·      C blunts protein glycosylation & sorbitol production 

·      Low intracellular C is a secondary nutritional deficiency that promotes the complications of DM 

·      This intracellular C deficiency is reversible 

Will supplementation be of value?


VITAMIN C & PROTEIN GLYCOSYLATION

 

©  12 healthy non-diabetic subjects

·      Vitamin C 1000 mg/day

·      No change in diet

·      Labs at baseline and three months 

¨ No change in fasting glucose or insulin  

¨  Plasma and RBC vitamin C levels 

 

Plasma C

RBC  C

Plasma:RBC

Baseline

73

60

1.26

Supplementation

 

 

 

1 month

109

59

1.92

2 months

119

74

1.55

3 months

93

84

1.14

 

 

 

 

Off C ´ 1 month

59

43

1.26

 


VITAMIN C & SORBITOL FORMATION 

Intracellular Sorbitol Accumulation

 

              Aldose Reductase      Polyol Dehydrogenase

      Glucose ------------------> Sorbitol ----------------------> Fructose

 

            ¨  Retina & Lens      ¨ Peripheral nerve

           ¨  Kidney                 ¨ RBC

 

·      Vitamin C and glucose are structurally similar 

·      Compete for biochemical attention 

·      C transport into cells is insulin dependent 

·      C transport is compromised by high glucose 

 

·      Diabetics are C and intracellular C deficient

 ·      Intracellular sorbitol predicts complications

  

Can we raise intracellular C with supplements?

 Will this lower intracellular sorbitol? 


VITAMIN C & SORBITOL FORMATION

 

© In healthy volunteers 

    · Measure rbc vitamin C & sorbitol levels

    · Supplement for 2 weeks with

          ¨ Vitamin C 500 mg

          ¨ C 500 mg with citrus bioflavonoids

          ¨ Vitamin C 2000 mg

    · Repeat the rbc measurements 

 

RBC Vitamin C

RBC Sorbitol

 

Base

 Tnt

 % D

 Base

 Tnt

 % D

C 500 mg

  33

  45

 +35

 20

  17

 -13

C 500 & BF

  32

  49

 +58

 20

  14

 -27

C 2000 mg

  33

 130

 +291

 19

   8

 -58

 

 © Type I and II diabetic patients 

 

Vitamin C

RBC Sorbitol

 

 

   

 

 Base

 Tnt

 % D

 Base

 Tnt

 % D

 

C 2000 mg

  32

  54

 +68

  50

  26

 -68

 

2000 & BF

  35

  56

 +60

  52

  31

 -40

 

 


VITAMIN C & SUGAR CONTROL 

 

©  27 type II diabetic patients under medical therapy  

    ·  90 day run in period 

    ·  Vitamin C 1000 mg b.i.d. for 90 days 

    ·  Usual diet, insulin, and drugs continued 

    ·  Randomized, double blind protocol followed     

 

FBS

HbA1c

Chol

HDL

Trigs

Run in

181

9.3

239

44.7

221

Vit C

163

8.5

228

42.4

195

% D

- 10%

- 9%

- 5%

- 5%

- 12%

 


 VITAMIN C - Summary 

 

1. Vitamin C metabolism is abnormal in diabetics   

2. Diabetics are vitamin C deficient  

3. C is involved in glucose metabolism  

4. Vitamin C supplementation will:  

       ¨ Increase intracellular C levels 

       ¨ Modestly improve glucose control 

       ¨ Decrease protein glycosylation 

       ¨ Block intracellular sorbitol accumulation

 


VITAMIN B12 VS RETINOPATHY

 

©  37 teenage type I diabetic patients 

·      15 received 100 g/day B12 with their insulin  

·      22 received insulin alone 

· Same diet and insulin dosages 

· Evaluate retinopathy at baseline, 1, & 2 years  

 

B12 Treated

Controls

Retinopathy

Yes

No

Yes

No

Pre- B12

15

0

8

14

DM duration

12

-

8.5

7.6

1 year B12

8

7

7

15

DM duration

14

12

9.7

8.5

2 years B12

7

8

10

12

DM duration

14

14

10

10



VITAMIN B12 VS NEUROPATHY

 

· B12 is necessary for normal nerve function

· Deficiency produces a reversible neuropathy

· B12 metabolism is deranged in diabetics  

©  12 diabetics with severe neuropathy 

·      Classic pain and numbness

      ·  Decreased DTRs and vibratory perception

      ·  Disordered balance

 

¨  15-30 g/day for 1-2 weeks & 1-2/week to follow

¨  Saline injections given to some ® no effect

¨  Glucose adequately controlled 

Complete remission

4

Improved

3

Near complete

3

Questionable

2

  

·      The majority had gastric hypochlorhydria

·      Constipation and diarrhea tended to improve

·      Impotence in two men resolved


LITHIUM

 

·       Used in the treatment of manic-depressive illnesses

·  Hypoglycemic reactions have been noted

·       Lithium deficiency present in some animal models

·       Insulinomimetic properties noted

 

Could lithium help with blood sugar control in diabetics?

 

©  Initially used to treat DM in 1924

©    33 type II and 5 type I diabetic patients

 

·  Admit to a metabolic ward and stabilize sugars

·  Hold diet and treatments constant

·  Add lithium carbonate 100 mg/day to their regimen

·  FBS and 1 hour PP at baseline & two weeks

 

 

Fasting Blood Sugar

One Hour Post-Prandial

 

Base

2 wks

% D

Base

2 wks

% D

Diet

137

128

- 6%

274

184

- 33%

Pills

157

108

- 31%

220

178

- 19%

Insulin

195

122

- 38%

223

164

- 26%

 

·       Tolerance good-transient thirst the first few days; liver,

    kidney, and lung function unchanged.

·       Some variability in response

·       Insulin requirement decreased in 50%


TAURINE

 

·      Amino acid present in animal food sources

·  Most abundant amino acid in heart muscle

¨ Taurine is effective in CHF

·  Taurine is an integral component of blood platelets

¨ Taurine decreases platelet stickiness in normals

¨ Potentiates the effect of aspirin and other agents

·       Taurine may interact with insulin receptors

        ¨ Platelet function is abnormal in diabetics

        ¨ Plays a role in diabetic vascular complications

 

Could Taurine improve platelet function in diabetics?

 


©   39 type I diabetics  

·       All well controlled; none with HTN or CV dz

·       Measure Taurine levels and platelet indices

·       500 mg Taurine t.i.d. for 90 days

·       Repeat lab studies

·       Obtain same labs from 34 control subjects 

 

Taurine

Plt Taurine

Arachacid 50

Controls

127

.99

.72

Diabetics pre

66

.66

.44

Diabetics post

93

.99

.72



ARGININE

                                        Nitric Oxide Synthase

      Arginine ----------------------> Nitric Oxide

 

© Natural Vasodilator           © Vasoprotective

© Antioxidant                        © Antithrombotic

  

Insulin, our metabolic hormone, is also a vasodilator

     · Insulin levels rise following a meal

    · Releases nitric oxide in arteries to muscle

    · Takes sugar & insulin to the cells that need them

 

Insulin mediated vasodilation is impaired in DM II 

    · Arginine transport is insulin dependent

    · Arginine is required to make nitric oxide

    · Nitric oxide is required for the vasodilation

 

Is intracellular arginine deficiency the culprit?

 Will arginine restore insulin mediated vasodilation?

 Could arginine protect vs vascular complications?



ARGININE

 

Arginine responsive cardiac conditions

 

 · Effort angina                   · Vasospastic angina

 · Hypertension                   · Heart failure

· Microvascular ischemia    · Endothelial dysfunction

 

© Trim & obese volunteers and type II diabetics  

       · Measure insulin mediated vasodilation

       · Measure overall insulin sensitivity

       · Repeat during arginine supplementation

 

© Change in blood flow

 

Base

Arg.

Trim

+21%

+ 25%

Obese

+  2%

+ 22%

DM II

-  1%

+ 22%

© D in Insulin sensitivity

 

Base

% ­

Trim

4.3-3.4

21%

Obese

9.7-7.8

19%

DM II

13.7-11

16%


VANADIUM

 

·       Essential trace element

¨   Widely distributed in nature

¨   Readily available in the food supply

¨   Necessary for proper cellular function

·       Insulinomimetic properties

¨   Promotes glucose uptake, utilization for energy,

    or storage as glycogen in muscle & liver cells

¨   Effective in experimental diabetes

 

Could Vanadium help control diabetes in humans?

 

©   Dr. Lyonne thought so in 1899

 


©   Overweight type II diabetic and non-diabetic individuals

·       2 wks placebo, then 3 vanadyl sulfate 50 mg bid

·       Diet and other therapies held constant

·       Labs before and after each treatment 

 

 

Controls

Diabetics

 

Placebo

VS

Plac

VS

% D

FBS

97

100

220

190

- 14%

HbA1c

< 6.2

< 6.2

9.4

8.8

- 6%

Chol

191

196

203

191

- 6%

Trig

333

410

626

498

- 14%

 


VEGAN DIET for NEUROPATHY

 

·       Weimar Institute in California

 ·       25 day intensive in-house program of nutritional intervention, vegan diet, and life-style modification

  

Effect in 21 diabetic patients

 

© Burning pain resolved in 17/21, on average at

    10 days(4-15); partial or slight improvement in 4 

© Numbness noticeably improved at 25 days 

©   FBS decreased from 168 to 115 

©   Cholesterol fell by 13%, triglycerides by 25% 

©   11 on insulin pre-diet 

¨   Dose decreased in 9

¨   Insulin stopped in 2 

© 7 on sulfonylureas pre-diet 

¨   3 converted to insulin

¨   Dose decreased in 2

¨   Discontinued in 2


  MANGANESE 

 

·       Co-factor in enzyme systems involved in sugar control, 

    energy metabolism, and thyroid hormone function 

 

·       Manganese depletion leads to diabetes in animals 

 

·       Diabetic humans have ½ the level of non-diabetics 

 

·       30 mg/day is recommended


ZINC

 

·       Critical to multiple steps in glucose metabolism        Insulin synthesis, storage, and release

       ¨ Insulin binding to liver, muscle, and fat cells

       ¨ Intracellular glucose metabolism 

·       Experimental zinc deficiency ® diabetes

       ¨ Insulin release and binding reduced

       ¨ Impaired wound healing - reversible 

·       Human zinc deficiency ® ¯ insulin and ­ glucose  

·       American diabetics are zinc deficient

       ¨ 2/3rds of us take in < 2/3rds of the zinc RDA

       ¨ Diabetics waste zinc in the urine

       ¨ Zinc wastage » severity of the diabetes

       ¨ Average level 65 vs 87mg/dl; 25% deficient

       ¨ Pancreatic zinc content 50% of non-diabetics

 

© Supplementing poorly controlled diabetics

 

Diet

Diet + 28 mg Zn

 

Before

After

Before

After

Zinc mg/dl

54

54

48

63

FBS mg/dl

212

218

233

202



 POTASSIUM

 

· Render rats potassium deficient ® 

       ¨ Glucose levels rise

       ¨ Insulin levels fall

 · Obese non-diabetics on a protein sparing fast ® 

       ¨ Glucose utilization decreases

       ¨ Insulin levels fall 

· Supplement potassium during the fast ® 

       ¨ Normal glucose and insulin metabolism   

·      Thiazide diuretics - HCTZ & dyazide 

       ¨ ­ glucose level in diabetics

       ¨  Induce hyperglycemia in non-diabetics             

 

Why?

 


   © Non-diabetic healthy volunteers 

     · Measure K+ level and insulin function 

     · HCTZ 100 mg/day ´ 10 days 

        ¨ With KCL 80 meq/day 

        ¨ Without KCL supplementation

 · Repeat the measurements 

 

80 meq KCL

No KCL

K+  pre

3.85

3.85

K+  post

4.35

3.05

FBS pre

92

93

FBS post

Nl

Nl

Glucose tolerance

Nl

Reduced

Insulin release

Nl

¯ by 20%

 



MAGNESIUM

 

· Second most abundant intracellular mineral

       ¨ Critical to energy formation

       ¨ Necessary for proper insulin function 

· Abundant in a natural diet

       ¨ Lost in food processing

       ¨ 85% take in < the RDA of 350 mg 

· Diabetics waste Mg+2 through the kidney

       ¨ Mg+2 deficiency is 2° the Diabetes

       ¨ ³ 25% diabetics are hypomagnesemic 

· Mg+2 deficiency causes/aggravates insulin resistance

       ¨ Mg+2 deficiency is a cause of diabetes

       ¨ DM 1/µ drinking water magnesium  

· Low Mg+2 is associated with diabetic complications

 ¨ Retinopathy                ¨ CV disease

 ¨ Platelet dysfunction     ¨ Hypertension  

                        Group

     Magnesium

Healthy volunteers

           1.04

DM without retinopathy

           0.88

DM - nonproliferative retinopathy

           0.77

DM - proliferative retinopathy

           0.66


 

 1. Is magnesium repletion possible in diabetics?  Yes   

2. Will this effect diabetic complications?            Yes 

·      Platelet function     ·  Hypertension  

·      Lipids                     ·  Overall CV risk  

3. Will Mg+2 favorably effect insulin release? 

4. Will Mg+2 favorably effect insulin sensitivity?

 


  ©  Overweight type II diabetic patients 

       · 3 week run-in:  Stable diet, all drugs on hold

       · Baseline labs

       · Magnesium 2 gm/day or placebo ´ 3 weeks

·      Two week washout period

·      Crossover to the other treatment

·      Repeat labs at the end of each treatment period   

 

Washout

Placebo

Magnesium

Plasma Mg

.79

.78

.86

RBC Mg

1.86

1.88

2.03

Insulin

9

9

10

Glucose

161

157

145


 NICOTINAMIDE

 Pathogenesis of type I diabetes

1. Viral or toxic damage to the b cells

2. Followed by auto-immune attack

3. Free radical oxidation is involved

 

Could an antioxidant, administered at diagnosis, prevent or delay progression to full blown DM?

 

Could an antioxidant, given to children at high risk, prevent the development of DM?

 


Nicotinamide

· Protects islet cells from oxidative damage 

· Converts into NAD, a cellular repairer 

· Promotes b cell regeneration in vitro 

· Prevents/delays experimental DM   

 


© 16 patients with newly diagnosed DM I

 

·      Intensive insulin therapy initiated

·      At one week add

       ¨ Placebo or

       ¨ Nicotinamide 3,000 mg/day

· Adjust insulin as required

· Randomized, double blind protocol  

 

Base

6 months

12 months

 

A1c

off I

U/kg

A1c

off I

U/kg

A1c

Placebo

14.9

22%

.22

7.7

0%

.35

8.6

Nicot.

14.4

71%

.07

7

43%

.23

6.4

   

© Meta analysis of 10 randomized studies 

 

Diagnosis

6 months

12 months

 

Ctrls

Nicot

Ctrls

Nicot

Ctrls

Nicot

C-pep

.62

.50

.47

.76

.32

.73

Insulin

.52

.50

.44

.43

.50

.49

HbA1c

12.9

12.5

7.2

6.5

6.3

6.2



 © Preventing type I diabetes in New Zealand 

· Screen 5-7 year olds for islet cell antibodies 

       ¨ 32,000 offered testing 

            § 20,000 underwent testing

                   ª 150 were Islet Cell Antibody positive

                       1,000 mg/day nicotinamide begun

            § 12,000 declined testing 

       ¨ 48,000 not offered testing 

 

Group

# DM/10,000 kids/year

20,000 -150 treated

8.1

12,000 declined screening

15.1

48,000 not screened

20.1

 


·      High ICA level precedes DM I by several years 

·      With a diabetic 1st degree relative Þ diabetes inevitable 

·      FPIR steadily declines » loss of b-cell function

 

Can Nicotinamide prevent or delay progression

to diabetes in high risk children?

 

·      Screen kids with a 1st degree diabetic relative 

¨ 562 children in Denver; 1500 in Aukland

¨ High level of ICA - Islet Cell Antibodies

¨ Still normal HbA1c

¨ FPIR below the 5th %ile

    Þ Not diabetic but progression inevitable

 

·      1st 8 in Denver were observed as a control group 

·      Denver kids 9-12 and all 10 Aukland kids received nicotinamide 1500-3000 mg/day 

·      Monitor both groups for progression to DM I 

Untreated control group

Age

FPIR

Months to DM

6

4

4

13

15

3

4

29

14

6

35

21

15

37

21

5

39

4

7

43

57

15

47

11

Mean 9

31

17

 

Nicotinamide group

Age

FPIR

Tnt-mos

FPIR-1 yr

FPIR-2 yr

10

3

25 - DM

0

7

4

12

24

32

-

10

14

2

-

-

6

15

17

14

-

8

21

18

18

-

12

24

26

35

24

2

26

5

-

-

6

27

6

-

-

8

39

13

-

-

6

43

11

-

-

1

44

12

-

-

3

47

27

79

128

5

56

26

98

72

8

66

30

83

-

Mean 6

31

17

 

 

 

Rate of progression to full diabetes 

 

Control

Nicotinamide

At one year

4/8

0/9

At two years

7/8

0/6

    

Probability of remaining non-diabetic 


 


NICOTINAMIDE

 

·      Prevents/delays pancreatic failure in type I DM

·      Preserve insulin release from the failing pancreas

 

Could Nicotinamide preserve insulin release and prevent/delay pancreatic failure in type II DM ? 

 

©  18 patients with poorly controlled type II DM 

·      High sugar despite max dose sulfonylurea therapy

·      All on diet; none on insulin

·      All with normal body weight 

¨ Measure FBS, MBS, HbA1c, and C-Peptide 

¨  Randomly divide into three groups: 

§  Insulin plus Nicotinamide 500 mg tid

§  Insulin plus Placebo tid

§  Current SU plus Nicotinamide 500 mg tid 

¨ Repeat measurements at three and six months 

¨ Patients blinded re Nicotinamide vs Placebo

  

   



Nicotinamide - Physiologic properties

· Protects islet cells from oxidative damage 

· Converts into NAD, a cellular repairer 

· Promotes b cell regeneration in vitro 

· Prevents/delays experimental DM

 

Clinical Effects 

· Prevents or delays pancreatic failure &

   progression to insulin dependent type I DM in 

       ¨ Children with Islet Cell Antibodies

       ¨ Children with ICAs and impaired FPIR 

· Delays & may reverse the disease in 

       ¨ Children with recently diagnosed type I DM 

· Preserves pancreatic function and synergizes

    with insulin and sulfonylurea drugs in 

       ¨ DM II failing sulfonylurea therapy


BITTER MELON 

· World wide 80% of diabetes care remains herbal 

· Mormodica charantia - centuries of traditional use 

       ¨ Anti-viral proteins - momorcharin & charantin

       ¨ b-sitosterol & diosgenin

       ¨ Insulin-like polypeptide 

© Vegetable insulin therapy for diabetics 

      · All medications held for 24 hours 

      · Draw fasting blood sugar 

      · Subcutaneous injection

            ¨ Saline - 5 healthy volunteers

            ¨ Saline - 5 diabetic controls

            ¨ Vegetable insulin - 9 diabetic subjects 

      · All subjects remained fasting 

      · Measure sugar values throughout the day      

               

 

0

.5

1

1.5

4

6

8

12

Controls

75

71

71

71

71

71

71

71

DM-Saline

210

200

200

199

198

199

198

198

DM-Insulin

295

232

222

206

150

176

189

210

 


· Onset of hypoglycemic activity - ½ to 1 hour

· Peak effect  

            ¨ 4 hours in type I diabetics

             ¨ 6 hours in type II patients


BITTER MELON 

© 12 type II diabetic patients 

     · Stable but elevated sugars on a diabetic diet 

     · Treat with Bitter Melon fruit

          ¨ Five with 5 gm powder tid » 100 mg ´ 3 wks

          ¨ Seven get aqueous extract of 100 mg ´ 7wks  

     · Measure post-prandial sugar at various points 

     · Monitor for liver, kidney, or CBC side-effects 

     · Monitor symptoms - Thirst, weakness, burning

 

                                       Results 

§ Symptoms improved & no side-effects  

§ Post-prandial sugar at 3 weeks

¨ ¯ by 25% - powder

¨ ¯ by 54% - aqueous extract 

§ Glyco Hb ¯ by 17%, from 8.4 to 6.9
      

 

Post-Prandial Sugar

Pwdr

Pre

Post

% ¯

Acq

Pre

Post

% ¯

1

297

154

48

6

422

97

77

2

331

262

21

7

236

99

58

3

280

217

23

8

380

118

69

4

424

377

11

9

280

150

46

5

200

137

32

10

380

125

67

Mean

306

229

25

11

450

100

78

 

 

 

 

12

250

115

54

 

 

 

 

Mean

343

115

66

     Fall in sugar over time - aqueous extract


 


ALOE VERA

 

Health benefits of Aloe Vera - well documented 

· Anti-inflammatory and immune system stimulation

· Lipid reduction in coronary patients

· Anti-anginal properties

· Said to be of value to diabetics 

     ¨ Diabetics is a major problem in Thailand

     ¨ Rely on expensive imported drugs

     ¨ Aloe gel effective and safe in animal studies

     ¨ Flavored juice - 80% aloe vera gel extract 

 

© 72 middle age type II diabetics 

       · Elevated FBS and abnormal GTT

       · Otherwise good health

       · No prior diabetic treatment 

¨  Divide into matched groups receiving:

· One tablespoon juice bid, or

· Sweetened placebo solution bid 

¨ FBS & lipids at baseline and every 2 wks ´ 6 wks

 

 

 

 

 

 

 

 

 


 Is Aloe Vera additive to drug therapy? 

© 72 middle age type II diabetics 

       · Elevated FBS and abnormal GTT

       · All on 10 mg glibenclamide  

¨  Divide into matched groups receiving: 

· Glibenclamide and one tablespoon juice bid, or

· Drug therapy and placebo juice bid  

¨ FBS & lipids at baseline and every 2 wks ´ 6 wks 

Results

§ Well tolerated - no subjects dropped out 

§ No effect on liver and kidney chemistries 

§ Effect on sugar, cholesterol, and triglycerides



ALOE VERA 

Health benefits of Aloe Vera - well documented 

· Anti-inflammatory and immune system stimulation

· Lipid reduction in coronary patients

· Anti-anginal properties

· Said to be of value to diabetics

· 80% aloe gel flavored juice used in Thailand  

Clinical Effects

In newly diagnosed or untreated type II diabetes: 

¨  Significant reduction in blood sugar

¨ Significant reduction in triglycerides

 

Type II diabetes poorly controlled with sulfonylureas 

¨     Significant reduction in blood sugar

¨    Significant reduction in triglycerides