Type-I diabetes mellitus (IDDM) is a chronic degenerative disease with compli Diabetes (IDDM), and type-II or non-insulin-dependent diabetes (NIDDM) …

Type-I Diabetes: Prevention of the Disease And Its Complications
Kathleen A Head, ND Abstract
Type-I diabetes mellitus IDDM is a chronic degenerative disease with complications which can be devastating There is an increasing body of research suggesting that prevention of IDDM by the avoidance of cows milk and by the supplementation of niacinamide may be possible This article will explore this research The course the disease takes also may not be inevitable Modification of diet and lifestyle factors as well as a comprehensive program of nutritional and botanical supplementation may help prevent the complications often encountered, such as neuropathy, retinopathy, nephropathy, micro- and macroangiopathy, and cataracts This article will review the research on specific nutrients, botanicals, dietary and lifestyle factors, and their application in type-I diabetes Alt Med Rev 1997;24:256-281

Introduction
Diabetes is defined as a disorder of carbohydrate metabolism caused by absence or deficiency of insulin, insulin resistance, or both, ultimately leading to hyperglycemia Diabetes mellitus is typically classified into two main subtypes: type-I or insulin-dependent diabetes IDDM, and
type-II or non-insulin-dependent diabetes NIDDM A more accurate way to differentiate the two would be to classify the insulin dependent diabetic as ketoacidosis-prone, and the non-insulin-dependent diabetic as ketoacidosis-resistant Type-I and II would be differentiated on immunological-etiological grounds with type-I referring to an immune-mediated condition, whereas type-II is non-immune-mediated1 This classification would result in the potential for three groups — a type-I insulin-dependent group, a type-I non-insulin-dependent group, and a type-II non-insulin-dependent group The type-I non-insulin-dependent group would encompass those non-obese diabetics for whom insulin is not yet required to prevent ketoacidosis but for whom islet cell antibodies are present in the blood This group can be considered to have type-I insulin-dependent diabetes in evolution The destruction of islet cells occurs gradually over time, so there is a delay in reaching the insulin dependency stage This article will focus on the prevention of type-I diabetes and its numerous complications In the United States, the prevalence is estimated to be about 026 per cent of the population by age 20 The ratio of
type-I:type-II varies depending upon the age group being assessed; the younger the age group, the greater the proportion of type-I diabetics In general, diagnosis of all types is made by meeting one of two of the following criteria: 1 Fasting plasma glucose levels of 126 mg/dl or greater on at least two occasions or, 2 a plasma glucose level of 200 mg/ dl or greater at two hours and on at least one other occasion during a 2-hour glucose tolerance test

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Some viruses seem to attack and destroy the beta cells directly, rather than It is believed that type-I diabetes has a initiating an autoimmune reaction 4 A genetic component which must be present for Venezuelan study conducted by Mijac et al susceptibility to occur Although the exact reported a mumps infection prior to the onset mechanism is unclear, transmission is believed of diabetes in 425 of subjects with IDDM to be autosomal dominant, recessive or mixed, vs a 125 incidence in control subjects4 although no mechanism has been proven If a Elevated levels of
Coxsackie virus IgM first-degree relative has IDDM, the child has antibodies have been reported in patients with a 5-10 chance of developing type-I diabenewly diagnosed type-I diabetes 5 Large tes1 It is believed that the susceptibility gene prospective studies have also found that resides on the sixth chromosome, with the exposure to enterovirus infections either in major alleles conferring risk being HLA-DR3, utero or during childhood may initiate betaHLA-Dw3, HLA-DR4, HLA-Dw4, HLA-B8, cell damage and subsequent type-I diabetes5 and HLA-B15 Other viral infections, including rubella and Secondly, an environmental insult, such as a virus, exposure to an allergen, or both, is believed to initiate the process in Table 1 The Pathogenesis of Type 1 Diabetes genetically susceptible individuals This Mellitus Adapted from Harrisons1 external influence precipitates an inflammatory response in the pancreas known as insulitis 1 Activated TAgent or response Event lymphocytes infiltrate the islet cells in the HLA-DR3, DR4, DW3, Genetic susceptibility pancreas Macrophages and T-cells appear DW4, B8, B15 to be implicated in beta-cell destruction via localized release of cytokines2 Cytotoxic
Virus ?, Cows milk Environmental event amounts of nitric oxide and reactive oxygen protein ? intermediates are also released, contributing to free radical damage to the Insulitis Infiltration of activated beta cells The initial steps in free-radical T lymphocytes induced islet cell death involve breaks in DNA strands and the activation of the Activation of autoimmunity Self nonself transition enzyme polyADP-ribosepolymerase PARP PARP is involved in DNA repair and consumes large amounts of NAD in Islet cell antibodies, cell Immune attack on beta cells mediated immunity the process The depletion of intracellular 3 NAD pools leads to islet cell death The Diabetes mellitus 90 beta cells destroyed inflammatory response is autoimmune alpha cells unopposed mediated and takes place on the surface of the insulin-producing beta cells such that these cells are no longer recognized by the chicken pox, had no statistically significant immune system Antibodies against the beta correlation4 The effect of routine vaccinations cells are produced, resulting in their as either a precipitating or preventive factor in destruction and the clinical appearance of diabetes has been alluded to by several
diabetes see Table 1 This destruction is researchers Further study in this area seems thought to occur slowly, over the course of 1 indicated several years in many cases Alternative Medicine Review x Volume 2, Number 4 x 1997 Page 257

The Pathogenesis of Type-I Diabetes

The Role of Alternative Medicine in Type-I Diabetes
There is increasing evidence that with appropriate genetic screening measures typeI diabetes may be prevented or halted if caught before total destruction of the beta cells occurs This will be discussed in further detail below Unlike type-II diabetes, which may be controlled without medication, alternative therapies are used as adjuncts to exogenous insulin in type-I diabetes Nutritional supplements, botanicals, diet, and lifestyle considerations have application in decreasing insulin requirements and helping to maintain more normal blood glucose levels In addition, they may prevent the onset of complications of hyperglycemia, including retinopathy, nephropathy, neuropathy and macro- and microangiopathy

Prevention of Diabetes
There is increasing evidence that typeI
diabetes can be prevented This involves intense screening of high-risk populations Since only 10 of cases are familial, screening of all people at risk for type-I diabetes is impossible without screening the entire population Evaluations involve both immunological and genetic screening Markers associated with future onset of diabetes, including islet cell antibodies ICA, glutamic acid decarboxylase antibodies GAD, antibodies against protein tyrosine phosphatase/IA2 and antibodies against the 37/40 K antigen, appear in the circulation years before clinical onset of disease2 Knowledge of the pathogenesis of IDDM and prevention studies suggest that progression to disease in antibody-positive individuals may not be inevitable; that the autoimmune processes directed against the beta cells may prove vulnerable to intervention Some of the research on prevention has centered around the use of immuno-suppressive therapy with the use of medications such as deflazacort, cyclosporin Page 258

A and azathioprine Use of these has not resulted in significant long-term improvement in beta-cell functioning, but only in 6-12 month remissions5,6 Other immunosuppressive and immunomodulating drugs are
in various stages of investigation5 Other strategies which seem to hold some promise include intensive insulin therapy7 and tolerance induction with injections of Bacille Calmette-Guerin BCG or GAD Neither BCG nor GAD injections have resulted in prevention of diabetes in humans;5 however, insulin therapy holds some promise When insulin was given to prediabetics, firstdegree relatives who were in late-stage prediabetes and expected to overtly manifest the disease within three years, the five who accepted the therapy remained diabetes free for 58 years One has subsequently developed diabetes The seven who refused insulin treatment were followed and all developed diabetes, six of them within three years5 The treatment involved a five-day course of intensive IV insulin every nine months, plus daily lowdose subcutaneous injections Treatment of newly diagnosed adolescent diabetics with conventional insulin therapy vs conventional plus 14-day intensive continuous IV insulin therapy yielded promising results by improving beta-cell function for one year8 It is postulated the insulin may act as an antigen, altering the autoimmune attack on the beta cells by repeated immunization There is
also a betacell rest hypothesis which suggests exogenous insulin gives the beta cells a rest, preserving their ability to secrete endogenous insulin In vitro it has been found that activated beta cells are more susceptible to immune attack by cytokines than are beta cells at rest 5 Vaccinations against potential viral triggers are also being explored The cows milk connection: Cows milk has been implicated as a possible trigger of the autoimmune response, resulting in antibodies to and subsequent destruction of

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beta cells in genetically susceptible people Karjalainen et al, in their 1992 study published in the New England Journal of Medicine, postulated on the specific mechanisms involved9 Comparing a group of 142 Finnish children with newly diagnosed IDDM with 79 healthy children and 300 adult blood donors, they found elevated IgG antibodies to bovine serum albumen BSA in all diabetic patients While they found low levels of this antibody in many healthy children, the concentrations in the diabetic patients were an average
of seven times higher9 They further identified a specific 17-amino-acid peptide ABBOS on the BSA molecule as the antigenic portion9 This portion differs from the sequence in human, rat or mouse albumins It is believed the antibodies cross-react with a surface antigen on the beta cell called p69 Infectious disease, most likely viral in nature, stimulates release of interferon gamma The interferon in turn is responsible for induction of the betacell surface antigen Thus, it appears cows milk protein, in conjunction with viral exposure, may be implicated in the etiology of IDDM They found only low concentrations of IgG antibodies to two other cows milk proteins, casein and ß-lactoglobulin The concentrations of these proteins were similar in both the diabetic and non-diabetic groups, implicating bovine serum albumin but not others A French study found a similar correlation between IgG anti-BSA antibodies and IDDM Levy-Marchal et al found elevated anti-BSA antibodies in 744 of newly diagnosed diabetics, in 20 of ICA positive nondiabetics, and in only 55 of controls10 Cavallo et al, on the other hand, found a connection between ß-casein and IDDM They found specific proliferation of
T-lymphocytes with bovine ß-casein in 51 24 of 47 of patients with diabetes compared to 27 1 of 36 of healthy subjects, demonstrating a positive response to ß-casein11 To further the inconsistency, Saukkonen et al, in a Hungarian

study, found a correlation between high levels of IgM antibodies to both bovine serum albumin and ß-lactoglobulin and IDDM The levels of IgG and IgA antibodies were similar in the diabetic and non-diabetic groups12 In a previous study in Finland, Saukkonen et al found patients with diabetes to have significantly higher levels of IgA and IgG antibodies to BSA, while levels of IgA antibodies to ovalbumin were not significantly different between diabetics and controls, and IgG levels were higher in controls13 Norris et al, in their Diabetes Autoimmunity Study in the Young, found no correlation between betacell autoimmunity BCA and early exposure to cows-milk protein Two hundred fifty-three children were screened for BCA, which was defined as elevated levels of insulin autoantibody, glutamic acid decarboxylase autoantibody, or insulinoma-associated islet tyrosine phosphatase autoantibody above the 99th percentile of 198 normal subjects There were no
differences between cases and controls in regard to exposure to cows-milk protein before the third or sixth month of life14 It should be noted, however, that although 253 children were screened for BCA, only a small group of 18 were antibody-positive Similarly, Mijac et al found no correlation between early exposure to cows milk and IDDM4 Perez-Bravo et al found a correlation between early before three months of age exposure to cows milk and other solid foods versus exclusive breast-feeding and IDDM15 Eighty diabetic children were compared with 85 non-diabetic children Fewer children in the diabetic group were exclusively breast-fed, and exposure to cows milk occurred earlier in the diabetic group15 Vaarala et al found an enhanced immune response to ß-lactoglobulin in 55 22 of 40 of newly diagnosed type-I diabetics compared with 22 7 of 32 of healthy children16 The Childhood Diabetes in Finland Study Group examined siblings of diabetics and found cows milk proteins to be elevated Page 259

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in those who also tested positive for islet
cell antibodies17 The researchers postulated an enhanced transfer of antigens across the gut barrier in these subjects In summary, many researchers have found statistically significant correlations between antibodies to cows milk protein, particularly to bovine serum albumin9,12,13,17 and the incidence of IDDM The avoidance of cows milk as a substitute for breast milk, at least in the first six months of life, seems warranted as a prevention for typeI diabetes Beta-cell preservation by nicotinamide: Nicotinamide niacinamide, a form of vitamin B3, has the capability in vitro of interrupting the pathogenetic mechanisms of IDDM Animal studies have yielded significant beta-cell protection from niacinamide Nitric oxide is believed to be a potent mediator in the pathogenesis of type-I diabetes as it exerts cytotoxic and inhibitory effects on pancreatic beta cells Using isolated rat islet cells, Akabane et al found that high concentrations of niacinamide 20mM but not low 5mM offered beta-cell protection18 Researchers used a casein-free diet plus nicotinamide in mice to prevent insulitis, a precursor to the development of diabetes They further found that when females were fed the
casein-free, soy-based diet at conception, rather than at day 21, a greater suppression of insulitis resulted, indicating that the maternal diet during gestation may be of importance in preventing diabetes in the offspring19 Since 1987, several studies have evaluated nicotinamides ability to prevent beta-cell destruction in patients newly diagnosed with type-I diabetes Niacinamides mechanisms of action include inhibiting the enzyme poly ADP-ribose polymerase PARP, preventing depletion of intracellular NAD, and quenching of free radicals9,20 PARP is responsible for cleaving NAD, causing NAD levels in the cytosol to fall to zero As mentioned previously, low intracellular NAD levels contribute to the death of islet cells Page 260

Pozzillo et al conducted a meta-analysis of 10 different controlled trials of nicotinamide on newly diagnosed IDDM patients Parameters for evaluating glucose control were C-peptide, glycosylated hemoglobin HbA1c, and insulin requirements C-peptide is that portion of proinsulin which remains after insulin is cleaved from the molecule It parallels in a 1:1 ratio the levels of endogenous insulin Exogenous insulin injections do not result in increased levels of
C-peptide One year after diagnosis, C-peptide was significantly higher in nicotinamide-treated patients; an average of 073 ng/ml vs 032 ng/ml in the placebo group No differences in insulin requirement or HbA1c were noted21 The only reported side effects included skin rash, transient elevation of serum transaminase, and recurrent hypoglycemia, each in two patients A double-blind trial on 56 newly diagnosed diabetics, using niacinamide and three to four insulin injections a day versus placebo and insulin, yielded mixed results There were no significant differences between the niacinamide and placebo groups for insulin requirement, glycosylated hemoglobin or C-peptide in children under 15 years of age When age at diagnosis was taken into account, patients over age 15 demonstrated significantly higher C-peptide secretion22 In another study, Pozzilli et al studied 80 patients Twenty-seven were treated with niacinamide, 25 with niacinamide plus cyclosporin, and 28 served as controls They were treated for 12 months; then treatment was discontinued and they were followed for another 12 months Insulin requirements doubled 12 months after discontinuing the nicotinamide or nicotinamide plus
cyclosporin, becoming identical to that of controls7 Furthermore, glycosylated hemoglobin values were similar to controls one year after treatment It appears that beta-cell function deteriorated after discontinuing the therapy In a small clinical trial conducted by Taboga et al, recently diagnosed subjects

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received insulin plus nicotinamide, three grams daily n11 or insulin alone n10 for two years Insulin requirements, bimonthly HbA1c, and half-yearly C-peptide evaluations were recorded No significant differences were observed between the two groups23 Results of the use of nicotinamide in early-onset type-I diabetes have been equivocal While niacinamide appears to help prevent beta-cell death, it does not intervene in the inflammatory process Vague et al reported that niacinamide extended the remission or honeymoon phase often seen after initial diagnosis, during which time the patients insulin requirement decreases or temporarily disappears However, the patients reverted to dependence on insulin within one year24 This is
similar to the effect of immunosuppressive drugs such as cyclosporin-A5 With the advent of screening methods capable of predicting which individuals are at high risk for developing IDDM, it may be possible to employ preventive measures prior to the onset of disease Screening involves testing for islet cell antibodies in first-degree relatives parent, child, sibling of individuals with IDDM First-degree relatives have a 10 chance of developing IDDM within five years The risk increases to 35 when ICA titers are greater than 20 Juvenile Diabetes Foundation units The presence of glutamic acid decarboxylase antibodies carries a risk of 17, and if both ICA and GAD antibodies are present the combined risk is greater than 9025 A population-based diabetes prevention trial was conducted with a group of 20,195 New Zealand school children Of these, 185 had ICAs, meeting the criteria for a niacinamide prevention trial The average follow-up time was 71 years Diabetes incidence of untested controls was 1607 124205 95 CI/100,000 person years at risk, while the incidence in the tested group, which was niacinamide treated when antibody positive, was 714 31-141 95 CI/100,000

person years Another
group of 13,463 individuals who were offered testing but refused had a diabetes incidence of 1848 101-310 95 CI The tested and treated group had 41 the incidence of diabetes of the other two groups combined It was concluded that, although the size of the effect had a wide confidence interval, the nicotinamide had a protective effect for the development of IDDM26 A word of caution must be interjected, however; niacin has been known to cause insulin resistance in normal subjects Greenbaum et al designed a study to determine if niacinamide might do the same The study involved eight islet-cell-antibody-positive relatives of type-I diabetics They were given two grams of niacinamide daily for two weeks Measurements of insulin sensitivity, insulin release, glucose effectiveness, and the constant for glucose disappearance Kg were taken at baseline, at the end of two weeks of therapy and after subjects had been off therapy for at least two weeks Nicotinamide administration caused a 236 decrease in insulin sensitivity P00227 Their conclusion was, the use of nicotinamide in subjects who are at risk of developing IDDM may be complicated by the drugs effects on insulin sensitivity This merits a
larger-scale investigation Further clinical trials should have at least one subgroup being tested for insulin sensitivity and insulin secretion Other preventive measures: Mathieu et al found a vitamin D3 analog 1 alpha-25OH2-20-epi-22-oxa-24,26,27-trishomovitamin D, in doses low enough to prevent hypercalcemia and bone demineralization, to prevent diabetes in mice The suggested mechanism of action was the restoration of suppresser cell activity28 Hypersecretion of insulin increases the likelihood of incidence of both type-I and II diabetes; inhibition of secretion helps prevent diabetes Both vanadium and zinc may act like insulin and

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decrease the hypersecretion of insulin, ultimately reducing the risk of developing diabetes29 Supplementation of vanadium as well as zinc also helps ensure that beta cells do not lose too much zinc during periods of stress29 There is evidence that low levels of zinc in drinking water may predispose toward IDDM30 The future of prevention: Three large clinical trials are planned or underway to
determine whether early intervention can prevent IDDM in persons at risk but who have not yet demonstrated clinical signs of disease In the Cows Milk Avoidance Trial, infants who have siblings with IDDM are randomized to receive either a cows-milk-based formula or a nonantigenic protein formula The Diabetes Prevention Trial-Type-I is randomly assigning people with a greater than 50 probability of developing IDDM to receive insulin injections or observation; subjects at intermediate risk will receive either oral insulin or placebo In the third trial, the European Nicotinamide Diabetes Intervention Trial, subjects at risk either receive nicotinamide or placebo31 Depending upon the results of these trials, large-scale screening of children for IDDM risk factors may be warranted

Preventing the Complications of Diabetes — Neuropathy, Nephro-pathy, Retinopathy, Microangiopathy, Cataracts — With Single Nutrient Intervention
There is a plethora of information on the use of nutritional supplements and botanicals to manage blood sugar and prevent diabetic complications The remainder of this article will examine many of the single nutrients and botanicals that have application in a
treatment protocol for type-I diabetes Some of these substances have been wellresearched, while important research remains to be done on many of them

Nutrients may be used to correct deficiencies which tend to prevail in patients with type-I diabetes In addition, they may be used in pharmacological dosages to affect a particular metabolic change The mechanisms of prevention involve inhibition of non-enzymatic protein glycation, inhibition of sorbitol pathway activity by aldose reductase inhibitors, prevention of hypoxia by vasodilators, inhibition of increased vascular permeability, and prevention of oxidative stress and free radical generation32,33 For nutrient effects at a glance, see Table 2 B vitamins: Levels of B vitamins, particularly pyridoxine, tend to be low or marginal in diabetics34-37 Thiamine B136 and cobalamin B1237 are occasionally low, while the metabolism of riboflavin B2 appears to be abnormal36,38 Due to abnormal metabolism of riboflavin, giving the activated form, riboflavin-5-phosphate, may be the most effective method of supplementation Pyridoxine levels appear to be low, particularly in patients with neuropathy39 The use of B6 for the treatment of diabetic
neuropathy has met with mixed results Jones et al reported on the use of 50 mg pyridoxine three times daily in 10 patients with diabetic neuropathy and signs of pyridoxine deficiency Seven of 10 patients had improvement in pain and paresthesias within 10 days, followed by a recurrence of symptoms within three weeks of discontinuing treatment This relapse abated when treatment was resumed40 A study by Levin et al found no significant effect from the use of B6 on 18 patients with diabetic neuropathy After four months of treatment, six of nine treated with 50 mg three times daily and four of nine in the placebo group reported significant relief There was no difference between the two groups with regard to motor nerve conduction velocity41 In the Jones study, all patients exhibited some pyridoxine deficiency, while in the Levin study only one patient had a low plasma pyridoxal phosphate level at the beginning of

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Table 2 Specific Nutrient Effects On Type 1 Diabetes
NUTRIENT NIACINAMIDE PYRIDOXINE RIBOFLAVIN THIAMINE
BIOTIN B12 FOLATE VITAMIN C VITAMIN E QUERCETIN/ QUERCETRIN NARINGIN HESPERIDIN INOSITOL SELENIUM CHROMIUM VANADYL SULFATE MAGNESIUM ZINC MANGANESE EFAs LIPOIC ACID ACETYL-LCARNITINE TAURINE PAK COENZYME Q PANTETHINE FUNCTION Protects beta-cells from destruction Correct a deficiency; neuropathy; retinopathy Diabetics have abnormal B2 metabolism; use R5P Correct a possible deficiency; neuropathy Correct deficiency of abnormal metabolism; neuropathy Correct a deficiency; neuropathy; lower homocysteine Lower homocysteine levels to prevent retinopathy and nephropathy Prevents protein glycosylation; antioxidant Aldose reductase inhibitor Prevents protein glycosylation; antioxidant; Reduces LDL oxidation Aldose reductase inhibitors Aldose reductase inhibitor Aldose reductase inhibitor Restores intracellular inositol; neuropathy Antioxidant Enhance insulin binding; reduce insulin requirement Has insulin-like effects — decreases serum glucose Restore levels typically low in diabetics May exert insulin-like effects; protects beta-cells Corrects a deficiency DOSAGE RANGE 1-3 grams/day 50-200 mg/day 50-100 mg/day 50-100 mg/day 8-16 mg/day 100-1000 mcg/day 1 mg/day 1-10 grams/day 400-800
IU/day 400-500 mg tid 400-500 mg tid 400-500 mg tid 500 mg bid-tid 200-400 mcg/day 500-1000 mcg/day 5 mg tid 500 mg/day 30 mg/day/2 mgCu 10-50 mg/day

Metabolism impaired in diabetics; vasodilation improves nerve conduction; microangiopathy; neuropathy 1-3 g/day Prevents protein glycosylation; antioxidant; Stimulates glucose uptake by muscle cells Restores myo-inositol levels; antioxidant; neuropathy; retinopathy Reduces abnormal platelet aggregation; restores depressed levels Lowers glucose levels in DM; helps prevent lactic acidosis Group of enzymes low in diabetics; neuropathy Lowers blood lipids in diabetics; neuropathy 300-600 mg/day 500-1000 mg tid 500 mg tid 2-3 g/day 30-100 mg/day 200-300 mg tid

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Figure 1 Glycosylation of Hemoglobin
R-NH2 HCO HCOH HOCH HCOH HCOH CH20H Hemoglobin A Glucose HCN-R HCOH HOCH HCOH HCOH CH20H Prehemoglobin A1c

the study It may be that pyridoxine is helpful for the treatment of neuropathy only in those patients who are deficient Since both studies were on small populations, study of a
larger population seems warranted Stanley Mirscky, MD, former president of the New York affiliate of the American Diabetes Association ADA, in his book, Diabetes: Controlling it the Easy Way , makes the clinical observation that 80 of diabetics with sensory neuropathy improved with thiamine supplementation Stracke et al reported on a 12-week study of 24 diabetics with polyneuropathy who were treated with benfotiamine a lipid soluble derivative of thiamine with high bioavailability, B6 and B12 Significant improvement in nerve conduction velocity as well as a trend toward improved vibrational perception were observed42 A longer term observation of nine patients for nine months supported these results Several rat and human studies have demonstrated the possible benefit of B12 for the treatment of neuropathy43-45 Biotin was given for 1-2 years to three diabetic patients suffering from peripheral neuropathy There was marked improvement in laboratory and clinical findings within eight weeks This suggests a possible deficiency or

disordered metabolism of biotin in the pathogenesis of diabetic neuropathy 46 A CO retrospective study of 18 diabetic patients over a HOCH period of from eight
months to 28 years found a HCOH significant absence of retinopathy in B6-treated HCOH individuals 35 Because of CH20H the low toxicity of the B vitamins, it would seem Hemoglobin A1c prudent to have all diabetic patients on a B-complex supplement Magnesium is necessary for the conversion of pyridoxine to its active form, pyridoxal 5-phosphate PLP Since many diabetics are deficient in this important mineral,47,48 supplementation with PLP may provide the most benefit for diabetics Since, in the abovecited studies, neither magnesium nor the activated form of B6 were used, the equivocal results may have been, at least in part, due to faulty conversion of pyridoxine Glycosylation and Antioxidants: It is believed that one of the mechanisms responsible for secondary complications of diabetes involves non-enzymatic glycosylation of proteins by glucose auto-oxidation49 It is the glycosylation of hemoglobin which offers a marker of long term blood sugar control see Figure 1 Glycosylated proteins generate free radicals, causing oxidative stress and tissue damage When a cell suffers oxidative injury, cytosol NAD and ATP levels fall Unless intracellular NAD levels can be restored, cell death
will ensue Antioxidants such as vitamins C and E have been shown to reduce protein glycosylation both in vivo and in vitro49,50 They also act as scavengers of free radicals generated by the glycosylated proteins49 Davie et al supplemented 12 non-diabetic subjects with one gram daily of ascorbic acid and demonstrated significant decreases of
H2C-NH2-R

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glycosylated hemoglobin 18 decrease and glycosylated albumin 33 decrease over a three-month period50 In contrast, Weykamp et al found no decrease is glycosylated hemoglobin when healthy volunteers were supplemented with 750 mg or 1500 mg of ascorbic acid daily for 12 weeks51,52 Jain et al found a significant reduction in glycosylated hemoglobin as well as a lowering of triglycerides in 35 type-I diabetics supplemented with 100 IU dl-alpha-tocopherol for three months53 Glutathione levels appear to be subnormal in the retinas of diabetics Ascorbic acid and alpha-tocopherol, fed to diabetic rats, significantly increased glutathione levels in the retina54 Carboxymethyl
lysine CML is a byproduct of oxidation of glycated proteins and is used as a marker for oxidative stress Formation of CML has been found to decrease with various antioxidants, particularly vitamin E, as well as the more recently researched potent antioxidant, lipoic acid55 Preventing oxidative damage: Antioxidants have an impact on diabetic complications via mechanisms other than prevention of protein glycosylation Cardiovascular complications of diabetes are, in part, due to small vessel damage by oxidized LDL Fuller et al found vitamin E, at a dosage of 1200 IU daily in the form of tocopheryl acetate, elicited significant reductions in LDL oxidation, but had no significant effect on lowering plasma glycosylated protein or glycosylated hemoglobin51 Kuznetsov et al found normalization of lipid peroxidation in hypertensive diabetics with alpha-tocopherol acetate56 Douilet et al found a significant protective effect of vitamin E and selenium on the kidneys of diabetic rats Plasma lipid peroxides, glucose, and TGs were also decreased57 Cary and McCarty report on 19/ 20 diabetic patients who had either improvement or no progression of retinopathy when supplemented with 500 mcg
selenium,

800 IU vitamin E, 10,000 IU vitamin A, and one gram vitamin C daily for several years58 Ongoing research is underway at this time The MICRO-HOPE study is examining the effect of an ACE inhibitor and vitamin E on the progression of renal and cardiovascular disease in 3,657 diabetics59 Lipoic acid thioctic acid is a physiological constituent of cell membranes and acts as a potent antioxidant, both within the cell membrane and in the cytosol Lipoic acid or its reduced form, dihydrolipoic acid, reacts with reactive oxygen species including superoxide radicals, singlet oxygen, hydroxyl radicals, peroxyl radicals, and hypochlorous acid60 Dihydrolipoic acid was found to protect rat islet cells from the destructive effects of reactive oxygen species and to suppress nitric oxide production, substances released by macrophages during insulitis3 Lipoic acid has been used extensively in Germany for the treatment of diabetic neuropathy61 Lipid peroxidation is increased in experimental diabetic neuropathy In vitro studies by Nickander et al found that lipoic acid significantly decreased lipid peroxidation of nerve tissue62 Lipoic acid stimulates glucose uptake by muscle cells in both
rat and human studies in a manner comparable to insulin61 Kahler et al divided a group of 80 diabetics suffering from complications into four groups One group served as the control group, one received lipoic acid 600 mg daily, one 1200 IU d-alpha-tocopherol, and one 100 mcg selenium All groups treated with antioxidants showed significant diminution of urinary albumin and thiobarbituric acid a reactive species and indicator of oxidative processes Neuropathy symptoms of thermal and vibratory sensitivities were also significantly improved63 The Sorbitol Pathway - The road less traveled or so we hope: The sorbitol pathway converts glucose to sorbitol and then to fructose It is especially active in diabetics as glucose rises in tissues that are not insulin

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Figure 2 The Sorbitol Pathway vitro test, they found 500 mg ascorbate alone decreased D-Sorbitol erythrocyte sorbitol by 126 vs a 272 decrease by ascorbate in a citrus fruit medium66 NADP NAD NADPH H Cunningham et al found similar results with lower doses of viSorbitol tamin
C Comparing IDDM adults Dehydrogenase NADPH with non-diabetics, 100-600 mg H ascorbate was given daily for 58 days Blood glucose control in the diabetics was moderate to poor D-Fructose Initially high RBC sorbitol levels doubled in the diabetic patients were brought to normal in 30 days sensitive — the lens of the eye, renal with vitamin C supplementation67 glomeruli, and peripheral nerves Excess Various flavonoid compounds, includglucose passively diffuses into cells and is ing quercetin, quercetrin, naringin, and hesreduced to sorbitol by NADPH with the help peridin have also been found to be aldose reof the enzyme aldose reductase In the presence ductase inhibitors68,69 ARIs have been found of NAD sorbitol is oxidized to fructose, to prevent diabetic cataracts70 The bioflacatalyzed by the enzyme sorbitol vonoid quercetin has been found, in vitro to dehydrogenase see Figure 2 Since sorbitol inhibit sorbitol accumulation in human does not diffuse passively through cell lenses71 Studies on diabetic animals have membranes, it accumulates, along with some found another bioflavonoid, quercitrin, to imfructose, within the cell, thus resulting in cell pede the course of cataract
formation72,73 A damage This elevation of sorbitol also results rat study did not yield positive results with the in a drop in myo-inositol inositol levels64 use of a quercetin for cataract prevention74 These events are believed to play a primary Refractive changes in the direction of hyperorole in the development of diabetic pia in diabetics have also been attributed to complications such as peripheral neuropathy, sorbitol accumulation in the lens Varma et al cataracts and nephropathy Animal and in vitro found flavonoids to significantly attenuate this studies have demonstrated the efficacy of process in diabetic rabbits75 Animal studies aldose reductase inhibitors ARIs in the indicate quercetins application in diabetes prevention of diabetic cataracts, retinopathy may also include normalization of glycemia, and nephropathy, and in early-stage diabetic reduction of total cholesterol and LDL,76 and neuropathy3 prevention of oxidation of LDL77 While there are numerous drugs that Lipoic acid has also been noted as an inhibit aldose reductase, there are also a aldose reductase inhibitor Transition metals number of single nutrient substances which do may be involved in activating the
sorbitol paththe same Vitamin C has been found, in way; ARIs, including lipoic acid, act as metal vitro 65 and in vivo 66,67 to inhibit aldose chelating antioxidants78 A constituent of licoreductase in RBC erythrocytes Vinson et al rice root Glycyrrhiza glabra has been found gave eight diabetic subjects 2000 mg daily of to exhibit potent aldose reductase inhibiascorbic acid for three weeks, and erythrocyte tion79,80 The component, isoliquiritigenin, was sorbitol levels decreased by 445 In an in found to decrease sorbitol levels in the sciatic Alternative Medicine Review x Volume 2, Number 4 x 1997
Aldose Reductase

D-Glucose

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nerve of diabetic rats This same study demonstrated a marked decrease in production of prostacyclin PGI2 by isoliquiritigenin79 This could have implications for mediation of not only diabetic neuropathy but also cardiovascular complications As previously mentioned, elevation of sorbitol within a cell results in a drop in inositol levels Untreated diabetics also appear to have altered inositol metabolism Six diabetic patients, before and after
insulin therapy, were compared with 10 non-diabetics The dietary inositol intake and fecal inositol excretion were similar in both groups However, the untreated diabetics exhibited a 10-fold increase in urinary inositol Insulin restored the urinary inositol excretion to normal Plasma inositol levels were high in untreated diabetics due to impaired intracellular transport This too was corrected by insulin therapy81 Lower intracellular inositol levels are thought to affect the development of neuropathy in several ways Experiments with streptozotocin STZ-induced diabetic rats indicate axonal transport of the enzyme choline acetyltransferase is reduced in the sciatic nerve When the lowered inositol content of the nerve cells was reversed by aldose reductase inhibitors or dietary inositol, the defective enzyme transport was reversed82 Another mechanism suggested by animal studies is that the slowing of nerve conduction, a hallmark of diabetic neuropathy, is caused by a low myo-inositol-related defect in neuronal sodium-potassium adenosine triphosphatase Na-KATPase83,84 This enzyme is responsible for generating action potentials across the nerve cell membrane, allowing for nerve impulse
conduction Decreased Na-KATPase activity in diabetic rat nerve is normalized by ARIs or dietary inositol85 Salway et al supplemented seven diabetic patients with 500 mg inositol twice daily for two weeks The amplitude of evoked action potentials in the sural, median, and popliteal nerves was increased by an average

of 160, 76, and 40, respectively, without an increase in conduction velocities during this short time period86 Sima et al fed normal rats a diet high in L-fucose, a competitive inhibitor of myo-inositol After 24 weeks, nerve inositol levels and Na-K ATPase activity decreased significantly The result was axonal atrophy, paranodal swelling and paranodal demyelination Dietary inositol supplementation prevented these structural changes and increased nodal remyelination87 Green et al concluded the reversible paranodal swelling seen in rat peripheral nerves was due to an inositol-related defect in Na-KATPase rather than the osmotic effect of sorbitol accumulation88 Inman et al addressed the hypothesis that diminished renal arteriolar reactivity to angiotensin II and norepinephrine NE in diabetes is the result of inadequate inositol incorporation into membrane phospholipids
The results of their rat study indicate improved reactivity to angiotensin II but not to NE in diabetic rats fed a myo-inositol-enriched diet89 D-chiroinositol but not myo-inositol significantly lowered plasma glucose levels in STZ-treated diabetic rats, normal rats fed a glucose load, and insulin-resistant monkeys90 Capillary basement membrane CBM thickening in retinal and glomerular capillaries has been implicated in the pathogenesis of diabetic retinopathy and nephropathy, respectively Tilton et al, in a study of diabetic rats, found no improvement in CBM thickening in retinal capillaries of rats fed an inositol-enriched diet The inositol-fed rats had an increase in glomerular CBM thickening over controls91 On the other hand, Chakrabarti and Sima found a diminution in retinal CBM width in rats supplemented with inositol, although other structural changes were not affected92 Mineral supplementation in type-I diabetes: Chromium is necessary for normal carbohydrate and lipid metabolism It is believed to enhance insulin binding to cell receptors Two-hundred mcg per day elemental Page 267

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Rights Reserved No Reprints Without Written Permission

chromium, from chromium picolinate, reduced the insulin requirement in 716 of 58 adults with type-I diabetes, as compared to 74 of type-II diabetics93 Another study comparing the same form and dose on type I and type-II diabetics found a greater difference between the effects on type-II and type I Requirements for insulin or other hypoglycemic agents were reduced in 572 of type-II diabetics compared to 336 of type I diabetics 94 Injections of glucose tolerance factor of which chromium is a constituent to STZ-diabetic rats, with no exogenous insulin, reduced blood glucose and free fatty acids within two hours95 Vanadium has been found to have important application in the treatment of IDDM Bosia et al report on vanadiums protective effect on diabetic cataracts and nephropathy in STZ-diabetic rats96 The protection was improved slightly with the addition of vitamin E Vanadium has insulin-like effects and is currently being considered for oral therapy It also reduces gluconeogenesis and increases glycogen deposition97 Vanadium salts induce sustained falls in blood glucose in diabetic rodents98 Insulin appears to affect the
metabolism of vanadium The half-life of vanadium varies among organs with insulin-sensitive tissue, such as liver and fat, which metabolize vanadium more quickly99 Toxicity studies on rats concluded vanadyl sulfate, in doses necessary to cause euglycemia, was not toxic after one year of administration; however, vanadium may be retained in organs for months after administration has ended100 IDDM patients tend to be low in serum magnesium A group of 71 people who had had diabetes for 10-20 years were divided into two subgroups depending on severity of retinopathy Hypomagnesemia was most pronounced in patients with the most severe retinopathy47 IDDM has been found to cause altered electrolyte metabolism and derangements in the parathyroid hormonevitamin D axis, resulting in lower ionized

calcium, magnesium, parathyroid hormone PTH, calcitriol, and osteocalcin in children with IDDM Saggese et al found magnesium to play a pivotal role in this phenomenon Supplementation of magnesium at 6mg/kg body weight in 23 IDDM children resulted in increased levels of calcium, magnesium, PTH, calcitriol, and osteocalcin101 Tarui found diabetic patients exhibited elevated urinary zinc levels which
were normalized with insulin treatment102 As mentioned previously, zinc may exert an insulinlike effect Injections of zinc chloride to alloxan-induced diabetic rats prevented the hyperglycemia generally observed 24 hours after alloxan103 Zinc appears to protect islet cells from destruction as well as to enhance the effect of insulin when the two are given in tandem Kosenko found the mean manganese content of whole blood of diabetics to be onehalf that of normal subjects104 Like zinc, manganese administration also prevented the postalloxan rise in blood glucose In the case of manganese, however, the beta cells were not protected from destruction In this same study, neither chromium nor cobalt protected rats from the diabetogenic effects of alloxan103 Other nutrient effects: Essential fatty acid metabolism is impaired in diabetics Delta-6-desaturase, the enzyme necessary to convert linoleic acid to gamma-linolenic acid GLA, is inhibited in diabetics A one-year study of 111 diabetic patients with mild neuropathy was conducted by Keen et al The group was divided, with half receiving 480 mg/day GLA and the other half receiving placebo After one year the change for all 16 parameters
measured was more favorable for the GLA group than the placebo group, with statistical significance for 13 of the parameters105 GLA has been found to enhance nerve conduction and blood flow in diabetic rats When GLA was bound to ascorbate to form ascorbyl gamma-linolenic acid the effect was

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40 times greater than with evening primrose oil and significantly greater than with GLA and ascorbate given together106 The effectiveness of essential fatty acids appears to be related to the vasodilatory effects, which improve nerve conduction107 PGE1 is one of the end products of GLA metabolism Intravenous PGE1 has been found to improve both subjective symptoms and vibratory threshold in patients with diabetic neuropathy108 Diets high in linoleic acid appear to decrease the progression of microangiopathy in diabetics109 It is advised that blood lipid levels be monitored when supplementing diabetics with essential fatty acids In at least one study, supplementation of type-I diabetics with omega-3 fatty acids in the form of
Max EPA resulted in an increase in total cholesterol On the other hand, a study of 18 type-I diabetics supplemented with cod liver oil, rich in omega 3 fatty acids, resulted in an increase in HDL levels and a decrease in triglycerides and VLDL There was no change in LDL level Olive oil decreased LDL, but increased VLDL and triglyceride levels In this same study, cod liver oil lowered blood pressure and partially normalized microvascular albumin leakage111 Beitz et al found cod liver oil at a dose of 68 g daily for two weeks decreased thromboxane B2 synthesis capacity of whole blood in typeI diabetics, but not in normal volunteers112 Acetyl-L-carnitine ALC has been found to enhance peripheral nerve function by normalizing nerve conduction velocity in STZdiabetic rats One mechanism appears to be restoration of myo-inositol levels Sorbitol levels in nerve cells remained high, however, so ALC was not acting as an aldose reductase inhibitor 113 ALC also reduced elevated malondialdehyde content of nerve cells, which is an indication of reduced lipid peroxidation These same researchers, in a different study, found ALC lowered sorbitol levels slightly, although they still remained high,
and had no effect on myo-inositol levels114

Lowitt et al found additional evidence that ALC works via another mechanism besides influencing the sorbitol pathway An electroretinogram measures the changes in electric potentials in the retina in response to light Rats with STZ-induced diabetes exhibited abnormal electroretinograms ALC significantly improved ß-wave amplitudes and decreased latencies of oscillatory potentials without affecting hyperglycemia or erythrocyte sorbitol levels115 The effect of lipotropic factors on diabetics was examined by Morrison A combination of 9 g betaine, 660 mg choline, 660 mg liver extract, and 36 mcg vitamin B12 daily was found to have an insulin sparing effect on diabetics, reducing their insulin requirement116 Franconi et al found that plasma and platelet taurine levels were low in IDDM patients Oral supplementation raised levels to normal They also found that the amount of arachidonic acid needed to induce platelet aggregation was lower in these patients than in healthy subjects Supplementation of taurine reversed this effect as well, reducing the effect of arachidonic acid on platelet aggregation In vitro experiments demonstrated that taurine
reduced platelet aggregation in diabetic patients in a dose-dependent manner, and had no effect on healthy subjects117 Pyridoxine alpha-ketoglutarate PAK has been found to lower blood glucose levels in diabetics Passariello et al noted an average blood glucose decrease from 216 mg/dl to 169 mg/dl after two weeks, and to 153 mg/dl after four weeks HbA1c levels also fell from an average of 139 to 113 after two weeks, and 94 after four weeks There was no change in the placebo group When PAK was discontinued, blood glucose and HbA1c returned almost to pre-treatment levels Furthermore, PAK reduced blood levels of lactate 366 in type-I diabetics Pyruvate levels were also decreased118 Although PAKs

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Table 3 Botanical Applications In Diabetes decrease of homocysteine levels A significantly higher Gymnema sylvestre Reduces insulin requirement and average percentage of diabetics with blood glucose; reduced HbA1c; regeneration retinopathy exhibit this of pancreatic beta-cells animals; lowers mutation Elevated homocertain
glycoproteins — GAGs cysteine levels cause cell Vaccinium myrtillus Lowers blood glucose; lowers triglycerides; injury to small vessels which decreases capillary permeability to prevent may contribute to the retinopathy; decreases abnormal development of retinopathy, glycoproteins as well as causing macroTrigonella foenum graecum Decreases urine glucose; lowers blood lipids; angiopathy in the cardiovascular system120 On the Momordica charantia Contains a polypeptide p-insulin with other hand, Agardh et al insulin-like effects; lowers blood glucose by increasing glucose utilization found no association between plasma homoCoccinia indica Lowers blood glucose by enhancing its cysteine levels and various utilization stages of retinopathy or early Tricosanthes dioica Lowers blood glucose animal models stage nephropathy in IDDM patients 121 Robillon et al Ginkgo biloba Membrane stabilization to prevent observed, in comparing 41 retinopathy type-I diabetics with 40 ageAgaricus bisporus Improves hyperglycemic effects of matched controls, that exogenous insulin diabetics actually had lower homocysteine levels than controls, and that mechanism of action is not fully understood, homocysteine
levels increased with age122 it is believed that it may activate the Krebs Hultberg et al found patients with procycle, enhancing glucose metabolism and liferative retinopathy had higher than normal pyruvate oxidation Whatever the mechanism, levels of homocysteine In this group, those PAK appears to improve glucose metabolism with minimal or no signs of nephropathy, while and to decrease hyperlacticacidemia, thus not as high as those with significant nephropapreventing lactic acidosis Researchers have thy 170 /- 59 mumols/l, still exhibited observed in type-I diabetics physical exercise slightly higher 121 /- 55mumols/l than induces an immediate and sustained rise of normal 110 /- 34 mumols/l homocysteine lactic acid in the blood stream118 DallAglio levels123 et al found infusions of PAK to type-I diabetics Elevated homocysteine levels, in immediately prior to isometric exercise patients with advanced nephropathy, are decreased the rise in serum lactate levels probably caused in part by decreased generally seen in response to exercise119 glomerular filtration rather than being a cause Elevated homocysteine levels appear of the nephropathy123 Turyn et al found that 120 to be a risk
factor for diabetic retinopathy insulin binding to rat submaxillary gland This may be due to a point mutation on the microsomes was enhanced in the presence of gene for the enzyme methylenetetraS-adenosyl-L-methionine SAM and was hydrofolate reductase This enzyme is partially suppressed in the presence of Simportant for remethylation and subsequent adenosyl-L-homocysteine124 The release of
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insulin in response to glucose was decreased in response to inhibitors of methylation such as DL-homocysteine, in rat pancreatic islet cells125 It is clear homocysteine contributes to diabetic complications in a subgroup of IDDM patients The connection between elevated levels and development of secondary complications of diabetes bears further study Coenzyme Q is important in the electron transport chain of the mitochondria Studies have found decreased levels of this group of enzymes in the liver mitochondria in diabetic animal models126 An oral dose of 10 mg Coenzyme Q7 for 3-13 weeks resulted in subjective
relief of pain and paresthesia, as well as improvement in threshold of vibratory perception, in patients with diabetic neuropathy127 Pantethine, a constituent of Coenzyme A and an active form of pantothenic acid, at a dose of 900 mg daily, has been shown to significantly lower total cholesterol, VLDL, and triglycerides in diabetic patients on dialysis128 Arsenio et al reported on a group of hyperlipidemic patients, a subfraction of whom were diabetics Pantethine was administered at a dose of 300 mg three times daily, with consistent gradual reductions over 12 months of triglycerides, total cholesterol, LDL, and apolipoprotein B, and increases in HDL and apolipoprotein A, including in the diabetic subgroup129 These are all consistent with a decrease in atherogenesis Shigeta et al studied the effect of 30-200 mg pantethine on vibratory perception thresholds in 16 patients with diabetic neuropathy130 Pantethine improved extremity paresthesias and pain in 33 of cases, and patellar reflex in 40130 For a concise summary of the nutrients discussed above, please see Table 2

The Influence of Botanicals on Type-I Diabetes
The use of botanicals has a long history in folk medicine for the
treatment of blood sugar abnormalities Prior to the development

of exogenous insulin in 1922, diabetes was managed with herbal medicines Many plants have been investigated in the last two decades in response to the World Health Organizations 1980 request that researchers re-examine traditional medicines see Table 3 Gymnema sylvestre, a plant native to India, has been used for the treatment of diabetes or madhu-meha honey urine for over 2000 years, and has been relatively widely studied since the 1930s A water-soluble extract of Gymnema leaf was administered to 27 type-I diabetics at a dose of 400 mg/day over a period of 10-12 months Insulin requirements were decreased by about one half, and average blood glucose was reduced from 232 to 152 mg/dl There was a reduction in HbA1c levels in the first 6-8 months, although the levels remained significantly higher than normal Similar reductions were noted in other glycosylated proteins Cholesterol and triglycerides were also lowered significantly, as was serum amylase, which is often more than doubled in diabetics In patients on insulin therapy alone, fasting glucose, HbA1c, blood lipids, glycosylated proteins, and serum amylase remained
high despite insulin therapy131 Numerous animal studies have corroborated these findings132-137 A Gymnema extract doubled the number of islet and beta cells in the pancreas of STZ-treated rats, lending credence to the theory that it increases insulin secretion by regeneration of the endocrine pancreas136 Some animal studies found Gymnema to be effective in lowering blood glucose only in mild to moderately diabetic animals, those who still retained some beta-cell activity; however, treatment with Gymnema in a severely diabetic group significantly prolonged life137 Abnormal glycoprotein composition of connective tissue basement membrane glycosaminoglycan GAG content has been implicated in diabetic complications such as microangiopathy and atherosclerosis

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Gymnema, in animal studies, lowered several glycoproteins, generally elevated in diabetics, to normal levels GAGs which are typically high in diabetics hyaluronic acid and heparin sulfate were lowered after administration of Gymnema, while the GAGs which are generally
depressed in diabetics chondroitin sulfate-A,-B,-C were elevated to normal134 Vaccinium myrtillus bilberry has long been used for the treatment of diabetes The biologically active constituents of bilberry include a family of flavonoids known as anthocyanosides Bilberry has been shown to lower plasma glucose by 26 in STZ-diabetic rats138 In this same study, it also lowered triglyceride levels by 39 While the hypoglycemic effects of bilberry are of interest in the treatment of diabetes, perhaps of more importance are its effects on stabilizing collagen139 and decreasing capillary permeability140 Increased capillary permeability, resulting in retinal hemorrhage with resultant abnormal collagen repair, is an underlying cause of diabetic retinopathy Bilberry can decrease abnormal collagen formation and capillary permeability, thus helping prevent retinopathy139 Thirty-one patients with various types of retinopathy were treated with Vaccinium myrtillus extract Reduction of both capillary permeability and tendency toward hemorrhage were seen in all patients, particularly those with diabetic retinopathy141 Fifty-four diabetic patients were treated with 500-600 mg/day of the extract for
8-33 months Almost total normalization of collagen polymers was achieved, as well as a 30 decrease in structural glycoprotein142 Via similar mechanisms, oligomeric proanthocyanidins from the seeds of Vitis vinifera may help prevent diabetic retinopathy143 Trigonella foenum graecum fenugreek has been studied, particularly in India, for the treatment of diabetes Defatted fenugreek seed powder was given to IDDM patients at a dose of 100 grams daily in two divided doses over a 10-day period The fenugreek-treated group exhibited a 54 dePage 272

crease in 24-hour urinary excretion of glucose, as well as a reduction in total cholesterol, LDL, VLDL, and triglycerides144 Animal studies have also demonstrated the hypoglycemic and hypolipidemic effects of fenugreek145-149 Momordica charantia bitter melon, bitter gourd is commonly found in China, India, and Africa, where it has a history of medicinal use150 The active, hypoglycemic constituents include charantin, obtained from an alcohol extract of the fruit, and a polypeptide called p-insulin plant insulin or polypeptidep isolated from the fruit and seeds of the plant The p-insulin consists of 166 residues containing 17 amino acids and has a
molecular weight of 11,000151 It is structurally and pharmacologically comparable to bovine insulin, and is composed of two polypeptide chains with disulfide bonds 150 Baldwa, et al studied the effect of p-insulin on nine diabetic patients and found an onset of action similar to bovine insulin 30-60 min and a peak hypoglycemic effect after 4 hours in type I diabetics, compared with 2-3 hours for regular insulin151 Several animal studies have confirmed the blood-sugar lowering effects of Momordica extracts152-155 while others have not155 The hypoglycemic effects of this plant appear to be, at least in part, due to extra-pancreatic activity, including increased glucose utilization by the liver;153 decreased glucose synthesis by depression of key gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6biphosphatase; and enhancement of glucose oxidation through the shunt pathway via activation of glucose-6-phosphate dehydrogenase154 Coccinia indica, in animal studies, has demonstrated blood-glucose lowering effects which appear to be via the same mechanism as Momordica154,155 Tricosanthes dioica has also demonstrated blood-sugar lowering effects in experimental animal models157
Ginkgo biloba contains membrane stabilizing flavones and anthocyanosides which, in animal studies, have been shown to prevent retinopathy158

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An animal study of the effects of twelve plants used traditionally in Europe for the treatment of diabetes yielded the following results: Arctium lappa burdock and Urtica dioica stinging nettle aggravated the diabetic condition; Anacardium occidentale cashew, Taraxacum officinale dandelion, Sambucus nigra elder, Trigonella foenum-graecum fenugreek, Humulus lupulus hops, Catharanthus roseus periwinkle, Salvia officinale sage, and Daucus carrota carrot had no effect on glucose homeostasis; and Ilex guayusa guayusa and Agaricus bisporus cultivated mushroom retarded the development of hyperglycemia in STZdiabetic mice, and reduced glycosylated hemoglobin, polydipsia, and weight loss Mushroom also improved the hypoglycemic effects of exogenous insulin 159 Other researchers also found Urtica dioica to exert a hyperglycemic effect in animal models160 Many other plants have been found to
exert hypoglycemic effects but only in type-II diabetics which will be the subject of a future article In animal models, differentiation is made by inducing either mild diabetes, which is meant to parallel type-II diabetes, or severe diabetes, the equivalent of type-I diabetes, in which there is little or no beta-cell activity remaining See Table 3 for a summary of botanicals in the treatment of IDDM

Dietary Factors in the Treatment of IDDM
Much of the research on dietary management of diabetes has centered on typeII diabetics, primarily because this type may be prevented and controlled by dietary changes alone The ingestion of a high complex carbohydrate, moderate protein, low fat diet versus a diet higher in fat and protein and very low in carbohydrate is controversial and undoubtedly depends on the individual and the type of diabetes in question The research on the pros and cons of each type of diet will be

the subject of a future article on type-II diabetes Originally the ADA promoted a low carbohydrate, high protein, moderate fat diet for patients with diabetes After considerable research was published on the benefits of a high complex carbohydrate, high fiber diet on the
glycemic index and lipid profiles in diabetes, the ADA began advocating diets containing 55-60 calories from carbohydrates161 A high fiber, high complex carbohydrate, low fat diet with the addition of 42 grams of gel fiber, in the form of glucomannan, was found to significantly improve glycemic control, insulin requirement, and HDL cholesterol levels in IDDM patients but not in patients on oral medication162 In another study, seven grams apple pectin in a shake with skim milk and vanilla given 10 minutes before a meal, decreased by 35 the insulin required to return glucose levels to normal in IDDM163 Sixteen grams guar gum and 10 g pectin was added to a meal containing 106 g carbohydrate This meal significantly decreased the postprandial glucose rise in three type-I diabetics164 Other researchers have not found pectin to help with long-term blood sugar control as measured by HbA1c165 In type-I diabetics, it appears it is not the high complex carbohydrate diet that is a factor in glycemic control so much as the type and amount of fiber being consumed On the basis of food diaries, diabetic patients without retinopathy ate significantly more complex carbohydrates, water-soluble fiber,
insoluble fiber, and glucose, and a lower proportion of calories from protein than did patients with retinopathy 166 Both water soluble and insoluble fiber significantly lowered mean postprandial glucose levels in diabetic dogs167 As mentioned above in the discussion of cows milk, diet may be a contributing factor in the development of type-I diabetes A Swedish study examined the diets of 339 children age 1-14 with newly-diagnosed

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IDDM, and compared them with 528 age- and sex-matched controls Foods were classified according to the protein, fat, carbohydrate, monosaccharide or disaccharide, nitrosamine, nitrate or nitrite, vitamin C, and fiber content, with the frequency of intake categorized as high, medium or low The relative risk of developing IDDM was calculated for the three frequencies of intake The results indicated that diets high in protein, carbohydrate not differentiated by type and nitrosamine compounds may influence the risk of developing IDDM in childhood168

cise will have the effect of lowering blood sugar
Care must be taken, however, as exercise may precipitate a hypoglycemic episode Assuming blood sugar levels are normal prior to taking insulin, the preprandial dose may need to be cut 30-50 when moderate exercise is anticipated170

Conclusion
Prevention of type-I diabetes is an exciting area of investigation, enabled by screening methods more sophisticated than were available in the past Three large clinical trials are planned or underway to determine whether early intervention can prevent IDDM in persons at risk but who have not yet demonstrated clinical signs of disease: The Cows Milk Avoidance Trial, the Diabetes Prevention Trial - Type-I testing the use of insulin on persons who have not yet manifested the disease, and the European Nicotinamide Diabetes Intervention Trial Depending on the results of these trials, large-scale screening of children for IDDM risk factors may be warranted There is considerable evidence that supplementation of type-I diabetics with specific nutrients and botanicals may significantly impact their chances of developing complications including micro- and macroangiopathy, retinopathy, nephropathy, neuropathy and cataracts In addition, the use of
botanicals and nutrients may significantly decrease insulin requirements Among the most promising nutrients are the B vitamins, vitamins C and E, chromium, zinc, magnesium, vanadium, lipoic acid, pyridoxine alpha-ketoglutarate, acetylL-carnitine, pantethine, quercetin, and essential fatty acids Botanicals which appear to be beneficial in the treatment of type-I diabetes include Gymnema sylvestre, Vaccinium myrtillus, Trigonella foenum graecum, and Momordica charantia Dietary interventions should include complex carbohydrates in the form of water soluble fibers, such as pectin and guar gum Blood sugar levels should be

General Lifestyle Factors
Smoking influences carbohydrate and lipid metabolism In a group of insulin-treated diabetics, 114 smokers were compared to 49 non-smokers Smokers had a 15-20 higher insulin requirement and serum triglyceride concentration This increase rose to 30 in heavy smokers169 Exercise may result either in hyper- or hypoglycemia In type-I diabetics, exercise prompts an immediate release of lactic acid as noted above as well as glucagon119 This release of glucagon may explain the rise in blood sugar noted by many type-I diabetics upon physical exertion A
rise in blood sugar upon exercise occurs particularly in those individuals with blood sugar levels above 250 mg/dl at the onset of exercise170 This can result in ketoacidosis Urine ketone levels should be checked before intense exercise is undertaken by these patients Another risk of exercise in diabetics, particularly those over age 40, is the possibility of unmasking an existing cardiovascular problem Ocular complications may also be precipitated by vigorous exercise in diabetics Exercise may benefit IDDM patients as well, by helping to lower blood glucose levels, increasing insulin sensitivity,170 and improving cardiovascular functioning In diabetics who maintain tight glucose control, exer-

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Saukkonen T, Savilahti E, Landin-Olsson M, Dahlquist G IgA bovine serum albumin antibodies are increased in newly diagnosed patients with insulin-dependent diabetes mellitus, but the increase is not an independent risk factor for diabetes Acta Paediatr 1995;84:1258-1261 Norris JM, Beaty B, Klingensmith G, et al Lack of association between early exposure to cows milk protein and beta-cell autoimmunity Diabetes Autoimmunity Study in the Young DAISY JAMA 1996;276:609-614 Perez-Bravo F, Carrasco E, Gutierrez-Lopez MD, et al Genetic predisposition and environmental factors leading to the development of insulin-dependent diabetes mellitus in Chilean children J Mol
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122 Robillon JF, Canivet B, Candito M, et al Type 1 diabetes mellitus and
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Shigeta Y, Hoshi M, Shichiri M Effect of pantethine treatment on vibratory perception in patients with diabetic neuropathy J Vitaminol 1966;12:299-302 131 Shanmugasundarum ER, Rajeswari G, Baskaran K, et al Use of Gymnema sylvestre leaf in the control of blood glucose in insulindependent diabetes mellitus J Ethnopharmacol 1990;30:281-294 132 Shanmugasundarum KR, Panneerselvam C, Samudram P, Shanmugasundaram ER Enzyme changes and glucose utilisation in diabetic rabbits: the effect of Gymnema sylvestre, RBr J Ethnopharmacol 1983;7:205-234 133 Shanmugasundaram ER, Gopinath KL, Shanmugasundaram KR, Rojendran VM Possible regeneration of the islets of Langerhans in streptozotocin-diabetic rats given Gymnema sylvestre leaf extracts J Ethnopharmacol 1990;30:265-279 134 Rathi AN, Visvanathan A, Shanmugasundaram KR Studies on protein-bound polysaccharide components glycosaminoglycans in experimental diabetes–Effect of Gymnema sylvestre, RBr Indian J Exp Biol 1981;19:715-721

135 Shanmugasundaram KR, Panneerselvam C The insulinotropic activity of Gymnema sylvestre, RBr Pharmacological Research Communications 1981;13:475-487 136 Prakash AO, Mathur S, Mathur R Effect of feeding Gymnema
sylvestre leaves on blood glucose in beryllium nitrate treated rats J Ethnopharmacol 1986;18:143-146 137 Srivastava Y, Bhatt HV, Prem AS, et al Hypoglycemic and life-prolonging properties of Gymnema sylvestre leaf extract in diabetic rats Isr J Med Sci 1985;21:540-542 138 Cignarella A, Nastasi M, Cavalli E, Puglisi L Novel lipid-lowering properties of Vaccinium myrtillus L leaves, a traditional antidiabetic treatment, in several models of rat dyslipidaemia: a comparison with ciprofibrate Thromb Res 1996;84:311-322 139 Boniface R, Robert AM Effect of anthocyanins on human connective tissue metabolism in the human Klin Monatsbl Augenheilkd 1996;209:368-372 140 Detre Z, Jellinek H, Miskulin M, Robert AM Studies on vascular permeability in hypertension: action of anthocyanosides Clin Physiol Biochem 1986;4:143-149 141 Scharrer A, Oher M Anthocyanosides in the treatment of retinopathies Klin Monatsbl Augenheilkd 1981;178:386-389 142 Lagrue G, Robert AM, Miskulin M, et al Pathology of the microcirculation in diabetes and alterations of the biosynthesis of intracellular matrix molecules Front Matrix Biol 1970;7:324-335 143 Werbach MR, Murray MT Botanical Influences on Illness Tarzana, CA:
Third Line Press; 1994:293 144 Sharma RD, Raghuram TC, Rao NS Effect of fenugreek seeds on blood glucose and serum lipids in type 1 diabetes Eur J Clin Nutr 1990;44:301-306 145 Ajabnoor MA, Tilmisany AK Effect of Trigonella foenum graceum on blood glucose levels in normal and alloxan-diabetic mice J Ethnopharmacol 1988;22:45-49 146 Ribes G, Sauvaire Y, Da Costa C, et al Antidiabetic effects of subfractions from fenugreek seeds in diabetic dogs Proc Soc Exp Biol Med 1986;182:159-166 147 Ghafghazi T, Sheriat HS, Dastmalchi T, Barnett RC Antagonism of cadmium and alloxaninduced hyperglycemia in rats by Trigonella foenum graecum Pahlavi Med J 1977;8:14-25

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148 Petit PR, Sauvaire YD, Hillaire-Buys DM, et al Steroid saponins from fenugreek seeds: extraction, purification, and pharmacological investigation of feeding behavior and plasma cholesterol Steroids 1995;60:674-680 149 Khosla P, Gupta DD, Nagpal RK Effect of Trigonella foenum graecum fenugreek on blood glucose in normal and diabetic rats Indian J Physiol
Pharmacol 1995;39:173-174 150 Cunnick J, Takemoto D Bitter Melon Momordica charantia J Nat Med 1993; 4:16-21 151 Baldwa, Bhandari CM, Pangaria A, Goyal RK Clinical trial in patients with diabetes mellitus of an insulin-like compound obtained from plant sources Upsala J Med Sci 1977;82: 3941 152 Khanna P, Jain SC, Panagariya A, Dixit VP Hypoglycemic activity of polypeptide-p from a plant source J Nat Prod 1981;44:648-655 153 Sarkar S, Pranava M, Marita R Demonstration of the hypoglycemic action of Momordica charantia in a validated animal model of diabetes Pharmacol Res 1996;33:1-4 154 Shibib BA, Khan LA, Rahman R Hypoglycemic activity of Coccinia indica and Momordica charantia in diabetic rats: depression of the hepatic gluconeogenic enzymes glucose-6phosphatase and fructose-1,6-bisphosphatase and elevation of both liver and red-cell shunt enzyme glucose-6-phosphate dehydrogenase Biochem J 1993;292:267-270 155 Day C, Cartwright T, Provost J, Bailey CJ Hypoglycaemic effect of Momordica charantia extracts Planta Med 1990;56:426-429 156 Platel K, Srinivasan K Effect of dietary intake of freeze dried bitter gourd Momordica charantia in streptozotocin induced diabetic rats Nahrung
1995;39:262-268 157 Chandrasekar B, Mukherjee B, Mukherjee SK Blood sugar lowering potentiality of selected Cucurbitaceae plants of Indian origin Indian J Med Res 1989;90:300-305 158 Droy-Lefaix MT, Vennat JC, Besse G, Doly M Effect of Gingko biloba extract EGb 761 on chloroquine induced retinal alterations Lens Eye Toxic Res 1992;9:521-528 159 Swanston-Flatt SK, Day C, Flatt PR, et al Glycaemic effects of traditional European plant treatments for diabetes Studies in normal and streptozotocin diabetic mice Diabetes Res 1989;10:69-73

160 Ramos RR, Alarcon-Aguilar F, Lara-Lemus A, Flores-Saenz JL Hypoglycemic effect of plants used in Mexico as antidiabetics Arch Med Res 1992;23:59-64 161 Anderson JW Recent advances in carbohydrate nutrition and metabolism in diabetes mellitus J Am Coll Nutr 1989;8:S61-S67 162 Vorster HH Benefits from supplementation of the current recommended diabetic diet with gel fiber Int Clin Nutr Rev 1988;8:140-146 163 Poynard T, Slama G, Tchobroutsky G Reduction of post-prandial insulin needs by pectin as assessed by the artificial pancreas in insulindependent diabetes Diabete Metab 1982;8:187-189 164 Jenkins DJ, Goff DV, Leeds AR, et al Unabsorbable
carbohydrates and diabetes: Decreased post-prandial hyperglycemia Lancet 1976;2:172-174 165 Gardner DF, Schwartz L, Krista M, Merimee TJ Dietary pectin and glycemic control in diabetes Diabetes Care 1984;7:143-146 166 Roy MS, Stables G, Collier B, et al Nutritional factors in diabetics with and without retinopathy Am J Clin Nutr 1989;50:728-730 167 Nelson RW, Ihle SL, Lewis LD, et al Effects of dietary fiber supplementation on glycemic control in dogs with alloxan-induced diabetes mellitus Am J Vet Res 1991;52:2060-2066 168 Dahlquist GG, Blom LG, Persson LA, et al Dietary factors and the risk of developing insulin dependent diabetes in childhood BMJ 1990;300:1302-1306 169 Madsbad S, McNair P, Christensen C, et al Influence of smoking on insulin requirement and metabolic status in diabetes mellitus Diabetes Care 1980;3:41-43 170 Fahey PJ, Stallkamp ET, Kwatra S The athlete with type 1 diabetes: managing insulin, diet and exercise Am Fam Phys 1996;53:16111616

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