The Cinula® is More Than Rationale Therapy in Diabetic Polyneuropathy

INTRODUCTION The Cinula® is a novel FDC of cunnulin PF 250mg, ALA 300mg Vit B12 100mcq, and Chromium (Cr), which has multiple therapeutic values for patients with obesity, prediabetes, the MetS, and T2DM. It can be used pathogenetically for patients with diabetic polineuropathy and oxidative stress (smoker etc). The link between increased body fat and insulin resistance has been generally recognized and accepted. It has become apparent that insulin resistance is actually associated with the increased in body fatness. The body composition of regional adipose depot-total body fat, deep subcutaneous fat, visceral fat– contributes most frequently to insulin resistance, and then prediabetes and the metabolic syndrome (the MetS) may pursue. The cinula®, the novel FDC cinnulin PF, ALA, and Vit B12, has biologic effects on body composition and prediabetes (Zeigenfuss et al 2006, 2007). The MetS is a “good example” of lifestyle related preclinical disease, and is an insulin resistant state associated with increased cardiovascular disease (CVD) risk. The MetS is usually been flanked by cardiometabolic risk factors, including various combinations of abdominal obesity, glucose intolerance, atherogenic dyslipidemia, hypertension prediabetes, and associated with a high risk of developing T2DM. The cinnamon extract has been demonstrated to improve the plasma glucose, A1C, and serum lipid of patients with T2DM (Khan et al 2003, Mang et al 2006, Zeigenfuss et al 2007). Antioxidant effects of a cinnamon extract in overweight or obese people with impaired fasting glucose have been studied by Roussel et al (2006). Alpha-lipoic acid (ALA), built in the cinula®, has antioxidant effects and has been demonstrated to be successful in the treatment of diabetic polyneuropathy, diabetic patients with insulin resistance, oxidative stress, hypertension, dyslipidemia and cardiovascular disease (Zeigler et al 2003, Midaoui et al 2002, Ametov et al 2003, Wollin et al 2003, Sola et al 2005, Young et al 2006). Vitamin B12, one component of the cinula®, has important roles in the treatment of diabetic neuropathy and also shows a pivotal role in the cognitive function. Chromium (Cr) content exists in the cinnamon, and it has been widely reported to play a role in the control of blood glucose of patients with diabetes mellitus which are due to its effects to improve insulin receptor and post receptor function.

Taken together, cinula®, a novel FDC of cinnulin PF, ALA, Vit B12, and Cr, with multiple therapeutic values can be indicated as adjuvant therapy for patients with obesity, prediabetes, the MetS, polineuropathy, oxidative stress, and T2DM.

I. AN OVERVIEW OF THE CINULA®
The cinula® is a novel fixed dose combination (FDC) of 250mg cinnulin PF (a propriety water soluble cinnamon extract), 300mg alpha lipoic acid (ALA), 100mcq cyanocobalamine C (Vit. B12) and chromium (Cr). Cumulatively, this cinula® may show several properties which are beneficial for patients with obesity, prediabetes, the metabolic syndrome (the MetS), T2DM and diabetic polyneuropathy. It is suggested that the FDC cinula® can reduce risk factors associated with such diseases (the MetS, T2DM, etc) and cardiovascular events. The multiple therapeutic values of the cinula® include (Khan et al 2003, Anderson et al 2004, Mang et al 2006, Ziegenfuss et al 2006, Hlebowicz et al 2007): 1. insulin sensitizer 2. lipid modulator 3. body composition-improver
4. antioxidant 5. anti-inflammation 6. anti-hypertension
7. polyneuropathy. Hence, cinula® is an appropriate FDC product for healthy glucose and lipids levels, blood pressure, body composition and antioxidant function.
This overview includes: I. Cinnulin PF II. Alpha Lipoic Acid
III. Vit. B12 IV. Chromium (Cr)
V. Therapeutic Values of the Cinula®

I. Cinnulin PF with Multiple Therapeutic Values Cinnulin PF is the only extract standardized for water soluble Double Linked – Polyphenolic Type A Polymers (DL- PTAP) identified by the USDA as being the active component. The water soluble cinnamon extract is able to filter out toxins found in whole cinnamon, making it safe for daily use. Taken together, cinnulin PF has broad beneficial therapeutic values in DHLAB (Khan et al 2003, Mang et al 2006, Roussel et al 2006, Ziegenfuss et al 2006), that means in the field of, or acts as: diabetology, hypertension, lipids (dyslipidemias), antioxidant, and body composition (decreased body fat, increased lean mass). On the basis of 3 studies (Mang et al 2006, Roussel et al 2006, Ziegenfuss et al 2006), cinnulin PF has been demonstrated (in metabolic syndrome, prediabetes, and T2DM) to decrease (+ 8%) fasting blood sugar, systolic blood pressure, and to improve lipid profiles (↓ TG, ↓ total cholesterol, ↓ LDL, but not HDL), various antioxidant measures (↑ FRAP, ↑ plasma SH groups, ↓ MDA) and body composition (↓ body fat, ↑ lean mass). The polyphenol type-A polymers (PTAP) extract from cinnamon have been reported to be able to counter insulin resistance through its several properties as listed below (Anderson et al 2004, Mang et al 2006, Meachler et al 1999).
1. Stimulate autophosphorylation of insulin receptor
2. Inhibit protein tyrosine phosphate (PTP-I)
3. Activate insulin receptor tyrosine kinase pathway (IRTK)
4. Activate phosphorylation of intracellular IRS-I and binding to P13-K
5. Increase insulin receptor P13K activity
6. Activate glycogen synthase for glycogen synthesis and inhibit glycogen synthase kinase 3

7. Activate nitric oxide pathway (enhanced insulin signaling) in skeletal muscle.
Beneficial effects of cinnamon on postprandial blood glucose, gastric emptying rate (GER) and satiety in healthy subjects have been demonstrated (Rousel et al 2006, Hlebowitz et al 2007). Delayed GER with prolonged post meal satiety by cinnamon leads to a lower post prandial blood glucose level. Khan et al (2003) and Mang et al (2006) reported that cinnamon improve blood glucose and lipids of patients with T2DM. Water-soluble polyphenolic type A polymers (PTAP) from cinnamon that increase glucose metabolism roughly 20-fold (in vitro) also display a potent antioxidant activity (Anderson et al 2004). Scientific antioxidant phytochemicals that have been identified in cinnamon include: catechin, epicatechin, camphene, eugenol, gamma-terpinene, phenol, salicylic acid, and tannins. It was thought that common species such as cinnamon, cloves might also have high chromium which biologically potentiate insulin activity. Antioxidant effects of a cinnamon extract (cinnulin PF) in overweight or obese patients with impaired fasting glucose have been studied by Roussel et al (2006). In a dose of 250mg two times per day for 12 weeks revealed (Ziegenfuss et al 2006): increased FRAP, increased plasma SH group, and decreased MDA. They supports the hypothesis that inclusion of cinnamon compounds in the diet could reduce diabetic cardiovascular risk factors.

II A. Alpha Lipoic Acid (ALA): At a Glance
Oral or intravenous administration of alpha lipoic acid has been demonstrated to be successful in the treatment of diabetic polyneuropathy, and diabetic patients with insulin resistance, oxidative stress, hypertension, dyslipidemias, and cardiovascular disease (Ziegler et al 1999, Midaoui et al 2002, Ametov et al 2003, Wollin et al 2003, Sola et al 2005, Young et al 2006). Alpha lipoic acid, also known as thioctic acid, is an endogenously produced compound thought to have strong antioxidant activity and may act as a scavenger of several free radicals including: hydroxyl radical (OH˚), hypochlorous acid, singlet oxygen, hydrogen peroxide, peroxynitrite, and nitric oxide (Ziegler et al 1999, Zang et al 2001, Midaoui et al 2002,). It has to be noted that reduced form of ALA, dehydrolipoic acid (DHLA), is the active compound providing nearly all the pharmacological benefits. DHLA is able to generate (recycle) other essential antioxidants (Vit. C, Vit. E, CoQ10, and glutathione) and its able to quence peroxyl and superoxide radicals. Taken together, the ALA/DHLA redox couple is one of the most powerful biological antioxidant systems, and this antioxidant couple has minimally 3 (three) beneficial properties (Midaoui 2002, Zang et al 2001, Schupke et al 2001): antioxidant, anti inflammation (inhibits TNF, reduces NFkB activation and adhesion molecules expression in human endothelial cells), and insulinomimetics (counter insulin resistance).

II B. ALA and Diabetes: In Brief
Alpha-lipoic acid (ALA), also known thiotic acid, contains two sulfur molecules that can be oxidized or reduced, such as the R- (the only synthesized naturally) and the S- isomers; in the text that follows, the term “ALA” refers to racemic ALA, while “R-ALA” or S-ALA” refers to the specific isomer. The two main functions of ALA (esp. R-isomer) are to play as a cofactor for several multi-enzyme complexes that catalyze critical energy metabolism reactions inside the mitochondria (for the synthesis of ATP, nucleic acid, and also Branched Chain Amino Acid (BCAA): leucine, isoleucine, valine as well as a potent antioxidant. Alpha-dihydrolipoic acid (DHLA) is the reduced form of ALA, and is the only form that functions directly as an antioxidant. Free ALA is rapidly taken up by cells and reduced to DHLA intracellularly. Because DHLA is also rapidly eliminated from cells, the extent to which its antioxidant effects can be sustained remain unclear. Although only DHLA functions directly as an antioxidant, ALA may have indirect antioxidant effects (Evans et al 2000, Hagen et al 1999, Khan et al 2003). Minimally six (6) potential therapeutics effects of ALA for several diseases can be summarized such as diabetes mellitus (DM), cataracts, glaucoma, ischemia-reperfusion injury, alcoholic liver disease, and other possible specific diseases. Acting as a potent antioxidant, DHLA was found to protect rat pancreatic islet cells from destruction by ROS. In vitro, ALA was found to simulate glucose uptake in muscle cells similar to insulin (mimetic effect or insulinomimetic), or to improve insulin sensitivity through several possible insulin signaling pathways (Midaoui et al 2002). ALA has been used extensively in Germany for the treatment of diabetic neuropathy; lipid peroxidation is believed to play a role in the development of this complication, and ALA was found to decrease lipid peroxidation of nerve tissue. Other mechanisms to explain its potential effect to prevent diabetic complications include the inhibition of “PAHA” (PKC, AGE, activated Hexosamine pathway, activated Aldose reductase) which means to inhibit the activation of PKC, the formation of AGEs, the activation of Hexosamine pathway, the activation of Aldose reductase, and to inhibit the activation of NFkB (Tjokroprawiro 2008, 2009).
Conclusions – R-ALA and its reduced form of ALA (DHLA) are potent antioxidants in both fat-and water-soluble mediums, and both (R-ALA and DHLA) function as a critical co-factor in several enzymes related to energy metabolism. Racemic ALA 600 mg/day may reduce symptoms and neurological deficits associated with diabetic neuropathy. Due to its multifunctional properties, it is most likely rationale to prescribe ALA for patients with T2DM, f.e.: to improve the insulin function and to protect β-cells of the pancreas from the “attack” of ROS.

II B1. Potential Clinical Benefits of ALA Six (6) biological effects of ALA (on diabetes mellitus) as an antioxidant are briefly described, and patients with diabetes may have many potential clinical benefits.
1. Scavenging Free Radicals
DHLA may prevent oxidative damage by interacting potentially damaging reactive oxygen species (ROS) and reactive nitrogen species (RNS).
2. Regenerating Other Antioxidants
DHLA is potent reducing agent, and has the capacity to regenerate a number of oxidized antioxidants to their active antioxidant forms. Specifically, DHLA is capable of reducing the oxidized form vitamin C, glutathione, and coenzyme Q 10, which are able to regenerate oxidized alpha-tocopherol (vitamin E), forming an antioxidant network. DHLA can be regulated from ALA through the activation of enzymes present in cells.
3. Chelation of Metal Ions
Both ALA and DHLA may chelate or bind certain free metal ions like iron and copper in way that prevents them from generating free radicals.
4. Increasing Intracellular Glutathione Levels
DHLA has been found to increase the uptake of cysteine (the precursor of glutathione synthesis) by cells in culture, leading to increased glutathione synthesis. DHLA is short-lived in intracellularly, however, DHLA may also improve intracellular antioxidant capacity by inducing glutathione synthesis.
5. Repair of Oxidative Damage
Alpha-anti protease (AP-1) is an inhibitor of the enzyme elastase. Oxidation inactivates AP-1, leading to increased activity of elastase and degradation of elastin in the lungs, a process that has been implicated in COPD. DHLA may reduce the enzyme, peptide methionine sulfoxide reductase (PMSR), which can reduce and reactivate oxidized AP-1
6. Regulation of Gene Transcription: NF-kappa B and AP-1)
NF-kappa B, a transcription factor of certain genes, that plays an important role in regulating genes related inflammation (Stentz et al 2004) and the pathology of a number of diseases, including atherosclerosis, cancer, and diabetes. ALA has been found to inhibit the activation of NFkB when added to cells in culture. AP-1 is another transcription factor that can be affected by both ROS and certain antioxidants within cells. DHLA has been found to inhibit the activity of ATP-1 by decreasing the expression of the gene c-fos, one of the proteins that make up the functional AP-1 complex. Based on to above descriptions, in clinical practice, ALA and DHLA as antioxidant couple may have many potential therapeutic benefits either for disease prevention (aging process) or for disease treatment (DM: insulin sensitivity, oxidative stress, diabetic peripheral neuropathy, and diabetic vascular complications). A component of potato extract firstly named “potato growth factor” in 1937, was identified as alpha-lipoic acid (ALA: occasionally referred to as thiotic acid), an eight-carbon disulfide containing a single chiral center.
ALA contains two isomers, the R- and the S- isomers: R-alpha-lipoic acid and S-alpha-lipoic acid. Only the R-isomer of ALA is synthesized naturally. ALA is produced is small quantities in liver cells and other tissue, where it functions as natural co-factor in multienzyme dehydrogenase complexes, such as pyruvate dehydrogenase (PDH) and α ketoglutarate dehyydrogenase; PDH is localized in mitochondria where it catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA, a critical step in oxidative glucose metabolisms (Konrad et al 1999). Taken together, ALA plays an essential role in mitochondrial-specific pathways that generate energy from glucose. ALA is reduced in vivo to its dithiol form, dihydrolipoic acid (DHLA). A compound that possessed biological activity. Both ALA and DHLA, as a redox couple, are potent antioxidants, and four distinct antioxidant actions have observed (Evans et al 2000):
1. ROS scavenger
2. capacity to regenerate endogenous antioxidants such as glutathione, vitamin C, and vitamin E
3. metal chelating activity
4. repair of oxidized proteins.
ALA is soluble in lipid and aqueous environments (Biewenga et al 1997A, 1997B). Due to its lipid solubility, ALA is highly effective in reducing free radicals, including lipid peroxides in cellular membranes. Because ALA is also soluble, it is able to gain access to the cytosol, where it effectively scavenger free radicals at their mitochondrial source.

II B2. ALA: Mitochondrial and Oxidative Stress Mitochondrial can be assumed as a “power house” (source of ATP production) in healthy people and in well-controlled diabetic patients, however, it will become a “crazy house” (source of free radicals production) in poorly-controlled patients with T2DM. It has been estimated that an individual produces approximately 1 kg of oxygen radicals per year, and the consequence of which is approximately 100.000 oxidative “attacks” on mitochondrial DNA per cell each day (Shigenaga et al 1994). The cumulative effects of these “attacks” on mitochondrial DNA is an increased frequency of mutation (Michikawa et al 1999) with its consequences. There are experimental data to indicate that ALA acts as an effective protective agent for mitochondria. In rats, ALA can partially reverse the decline in mitochondrial function and the increase in oxidative stress associated with aging (Lykkesfeldt et al 1998, Hagen et al 1999). II B3. ALA: Oxidative Stress and Diabetes Diabetes Mellitus is strongly associated with increased oxidative stress which could be a consequence of either increased production of free radicals or reduced antioxidant defenses. Oxidative stress may cause mitochondrial damage or oxidative damage (Schrauwen et al 2004). There is considerable evidence to indicate that hyperglycemia may cause glucose autooxidation in the mitochondria and increased ROS production may pursue. Minimally, there are 4 (four) biochemical pathways of ROS to destroy all cells and tissues of the body which may result in diabetic vascular complications including diabetic nephropathy and neuropathy. These 4 pathways that can be abbreviated as “PAHA” are listed below (Tjokroprawiro 2001, 2003, 2004, 2008, 2009):
1. PKC (activated by DAG = diacylglycerol)
2. AGE (increased formation)
3. Hexosamine pathway (activated)
4. Aldose Reducatase (activated poliol pathway)
Oral ALA supplementation 600 mg/day has been found to decrease NF-kB (transcription factor for inflammation) activation in the white blood cells of type 1 diabetics and patients with diabetic nephropathy. ALA has also been found to prevent the formation of AGEs in the test tube. An intervention trial in 10 patients with DM found that plasma lipid peroxides were significantly lower after taking 600 mg/day of ALA orally for 60 days compared to baseline. Oxidative stress is not only associated with diabetic complications, but has been also linked to insulin resistance. In vitro, oxidative stress causes insulin resistance at multiple levels. An additional potential target of oxidative stress is likely to be the β-cell. Therefore, it is logical to recognize that oxidative stress (e.g., H2O2) damages β-cell mitochondria and markedly blunts insulin secretion (Maechler et al 1999). Taken together, it is rationale to prescribe antioxidant including DHLA, vitamin C and E, and N-acetyl-L-cystine for patients with DM to protect β-cells of the pancreas from the “attack” of free radicals.

II B4. ALA: Its Roles in Insulin Action Data from animal studies suggests that the R-isomer may be more effective in improving insulin sensitivity than the S-isomer, but this possibility has not been tested in any published human trials. It was ingested that the beneficial effects of ALA to the insulin action might be attributed to the presence of the sulfhydryl groups of ALA. Following oral dosing of ALA 600 mg/day, the plasma-concentratin of ALA is typically in the range of 10-25μM (Breithaupt-Grogler et al 1999). Importantly, the effect of ALA is achieved at a potency that is consistent with its therapeutic plasma concentration. The possible benefits of ALA on insulin signaling pathways are:
1. increases tyrosine phosphorylation of insulin receptor tyrosine kinase (IRTK) and IRS-1
2. increases PI3-kinase activity
3. increases protein kinase B = PKB (Akt)
4. stimulates the plasma membrane-targeted translocation of GLUT 1 and GLUT 4.
In contrast to the effects of ALA, the possible mode of actions of oxidative stress (free radicals) to impair insulin action are:
1. to increase phosporylation of insulin receptor substrates on discrete serine or threonine sites (the activation of serine / threonine kinase signaling cascades) the tyrosine phosphorylation
2. to decrease the extend of the tyrosine phosphorilation.
In conjunction with this possibility, maintaining the intracellular redox balance might also serve to block the stress-induced oxidation and inactivation of protein tyrosine phosphatases (PTPases). It can be concluded that the protective effect of ALA and DHLA on oxidative stress-induced insulin resistance may related to their ability to preserve the intracellular redox balance, acting either directly or through other antioxidants such as glutathione.
II B5. ALA and Diabetic Neuropathy ALA levels are decreased in humans with uncontrolled diabetes and in some patients with polyneutritis and cardiovascular disease. Its is likely provided an additional rationale for administering ALA to patients with diabetes, (i.e., replacement therapy). ALA has been prescribed in Germany for over 30 years for the treatment of diabetes-induced neuropathy (Biewenga et al 1997A, Ziegler et al 1999, 2006, Dyke 2003).
The overall conclusions of clinical studies evaluating ALA for the treatment of diabetic neuropathy are:
1. 3-week treatment with iv ALA (600 mg) reduced the main symptoms of diabetes-induced polyneuropathy
2. the effects is accompanied by an improvement in neuropathic deficits
3. oral treatment with ALA (800-1800 mg per day) for 4-7 months appears to improve neuropahthic deficits
4. preliminary data also suggest an improvement in motor and sensory function in lower limbs
5. ALA has an excellent safety profile at oral doses up to 1800 mg/day.
Taken together, these results suggest that i.v administration of ALA is more efficacious than oral one. A pivotal multicenter trial, Neurological Assessment of Thiotic Acid in Neuropathy (NATHAN) study, is in process in Europe and North American to evaluate the effects of oral ALA to slow the progression of diabetic neuropathy. To date, the available research suggests that oral doses of at least 600 mg/day of ALA may offer some benefit in the alleviation of neuropathic symptoms and deficits, especially when used in conjunction with excellent glycemic control.

II B6. ALA and Endothelial Function In one study, intra-artherial infusions of ALA improved endothelium-dependent vasodilatations in 39 diabetic patients, but not in 11 healthy controls. Oral supplementation of 1200 mg/day of ALA for 6 weeks improved a measure of capillary perfusion in the fingers of 8 diabetic patients with peripheral neuropathy. In uncontrolled, non-randomized study of 84 diabetic patients, plasma thrombomodulin levels, a marker of compromised endothelial function, decreased significantly in the 35 diabetics that took 600 mg/day of ALA orally over 18 months, while thrombomodulin levels increased significantly in those that did not take ALA over the same period. III. Vitamin B12: In Brief At present, it is known that Vit. B12 deficiency is common and that its prevalence increases with age (Loikas et al 2007, Hin et al 2006, Schupke et al 2001). The Banbury B12 study concluded that low Vit. B12 levels are associated with cognitive impairment and missing ankle tendon jerks in older people in the absence of anemia (Hin et al 2006). Diabetes is associated with neuropathy, cognitive impairment, several causes of anemia, and decreased or absent ankle reflexes (Hin et al 2006, Voelcker-Rehage et al 2006). Metformin (for patients with DM) is an invaluable antihyperglycemic agent and it also has cardioprotective properties. The diabetologist and neurologist must be aware of the possibility of metformin – associated B12 deficiency (+ 27% patients exposed to long-term treatment with metformin) in its users (esp. more than one year) who suffer cognitive impairment and peripheral neuropathy (Weir et al 1999, Hermann et al 2004, Eussen et al 2005, Ting et al 2006).
The Vit. B12 intrinsic factor complex uptake by ileal membrane receptors is known to be Ca-dependent, and metformin affects Ca-dependent membrane action. It was reported that increated intake of calcium reverses Vit. B12 malabsorption induced by metformin (Bauman et al 2000). The lower dose of oral Vit. B12 required to normalize mild Vit. B12 deficiency is more than 200 times (+ 600g) greater than the recommended dietary allowance, which is approximately 3g daily (Eussen et al 2005). Or one tablet Neurobion® which contains 1.000mcq will be able to cover such a Vit. B12 deficiency. One study reported, Vit. B12 deficiency can be treated by monthly i.m. injections of 1.000g cyanocobalamin administered orally. Deficiency of vitamins B12, folate, and pyridoxine are common in demented patients, whether due vascular dementia (well known to be associated with homocysteinemia) or to Alzheimer‟s disease; these vitamins are known to induce impairment of cognitive function (Loikas et al 2007, Watanabe 2007, Weir et al 1999). Vitamin- B12 may improve the nerve regeneration and restores nerve function such as (Summarized: Tjokroprawiro 2008, 2009)
1. improved neurotropic activity
2. increased retention in nerve tissue
3. decreased neurotoxic cytokines
4. improved myelin structure.
The low B12-Vitamin, particularly in combination with low folate, may constitute a risk-increasing factors for the development of TIA and stroke.

IV. THE COMPLIMENTARY TOPICS: CHROMIUM, ALA, AND VIT B12 The following topics and description are made in order to be complementary with previous information about cinnulin PF, ALA, and Vit. B12. Due to the chromium content exits in the cinnamon, the roles of chromium in the treatment of diabetes will be shortly illustrated. IV A. The Roles of Chromium in the Treatment of Diabetes Increase intakes of simple sugars and fats, which are known to decrease insulin sensitivity are likely causes of the increasing incidence of T2DM. Of micro- nutrients, the one most limiting the diet and shown to have the largest effects on the signs of T2DM in humans is chromium (Anderson 1998). Chromium (Cr) was firstly reported to play a role in controlling blood glucose in the late fifties and several recent studies have documented its effects in people with glucose intolerance and T2DM. Improved fasting and glucose tolerance with lower or similar levels of circulating insulin have been reported in several studies involving Cr supplementation of people with varying degrees of glucose intolerance. In a follow-up survey, the fasting and postprandial glucose, and diabetic symptoms of 833 patients with T2DM were monitored for up to 10 months following Cr supplementation 500 ug/day Cr as chromium picolinate (Cheng et al 1999). All subject were on hypoglycemic medication and/or insulin. Fasting and post prandial glucose improved in more than 90% of the subjects and similar improvement occurred after 1-10 months. Symptoms of diabetes including fatigue decreased up to 12% or 88% of patients are successful. No adverse reactions were observed. These data confirm the safety and beneficial effects of supplemental chromium. Ravina et al (1999) in the recent study demonstrated that supplemental Cr 200 ug 3 times daily (as chromium picolinate) was useful in the control of steroid-induced diabetic patients. Most of patient (94%) with steroid-induced diabetes could be controlled by supplemental Cr, 200 ug of Cr as Cr picolinate, 3 times daily. Prior to the initiation of supplemental Cr, hypoglycemic agents were also reduced 50%. Following two weeks of 600 ug per day of supplemental Cr, daily Cr intake was reduced to 200 ug. Ten percent (10%) of the 50 patients were able to stop all forms of hypoglycemic agents, and good glycemic control could be maintained by taking 200 ug of chromium daily.
Over production of insulin in the chromium-deficient rats was demonstrated by Striffler et al (1999). The hyperresponsiveness in this experimental rats is likely the result of decreased peripheral tissue sensitivity of insulin. In a recent double-blind, placebo-controlled study involving 180 patients with T2DM, supplemental Cr (Cr picolinate 1000 ug/day compared with 200 ug/day) was shown to improve fasting glucose, insulin, post prandial glucose, AIC, and cholesterol (Anderson et al 1997). The two-hour blood glucose values were significantly lower after 2 months in the group receiving 1000 ug/day supplemental Cr, and after 4 months were lower in both groups receiving supplemental Cr. Insulin was significantly lower in both Cr group after two and four months. Plasma total cholesterol also decreased after consuming 1000 ug of Cr per day for 4 months. AIC was 8.5 ± 0.2% in the placebo group, 7.5 ± 0.2% in the 200 ug group and 6.6 ± 0.1% in the group receiving 1000 ug of Cr/day for four months. In a follow-up study involving more than 800 patients with T2DM, blood glucose and symptoms of DM including excessive thirst, urination and fatigue improved over 80% of the patients (Cheng et al 1999). Improvement in glucose, insulin and related variables in response to Cr normally occur within a few weeks or less. However, improvement in blood lipids may take longer. In the study of Abraham et al (1992) involving supplement (250 ug per day of Cr as Cr Chloride) of 25 patients with diabetes and atherosclerotic diseases, improvement in HDL and triglyceride took more than 6 months. A limited number of studies (Rabinowitz et al 1983) reported no beneficial effects of supplemental Cr which is usually not adequate for patients with DM, especially if it is in a form with low absorption. Pregnancy is a state of insulin resistance and if a women‟s pancreas can not increase insulin production and/or efficiency to compensate for the increasing needs throughout pregnancy, gestational diabetes mellitus (GDM) occurs. Jovanovic et al (1999) in the study of 30 women with GDM (20-24 gestational weeks) with supplemental Cr-picolinate of 0, 4, 8 ug Cr/Kg BW for 8 weeks concluded that:
1. Chromium supplementation in GDM improved glucose intolerance and lowered hyperglycemia
2. Chromium effects in the group receiving 8 ug Cr/Kg BW were greater than those receiving 4 ug/Kg BW
3. Chromium supplementation may be as an adjunctive therapy for patients with GDM when dietary regimens are not sufficient to achieve good glycemic control.
Beneficial effect of supplemental Cr on patients receiving TPN (total parenteral nutrition) have been reported by Freund et al (1979), and Brown (1986). Chromium is now routinely added to TPN solutions and Cr recommendations for patients with TPN have been reviewed (Anderson 1995). Peripheral neuropathy and fractional glucose clearance were improved after supplementation Cr (250 ug/day chromium chlorate).

IV B. Possible Mechanisms of Action of Chromium Possible mechanisms of Cr in the control of blood glucose are due to the improvements of receptor and post receptor actions (Davis et al 1997, Cefalu et al 999).
1. Supplemental Cr leads to increased insulin binding to cells due to increased insulin receptor number.
2. Improved glucose utilization (peripheral) and sensitivity of beta-cell (central) have also been demonstrated. Chromium activates IRTK (Insulin Receptor
Tyrosine Kinase) 8-fold in the presence of insulin but does not in the absence of insulin.
3. Chromium inhibits phospho tyrosine phosphatase-1 (PTP-1) (in rat: homolog of a PTP-IB) that inactivates the insulin receptor (IR).
Conclusions: Increased affinity to insulin receptor (IR), increased IR-number, activation of IRTK, and the inhibition of PTP-1, all of these lead to the increased insulin sensitivity. The Reference Dose established by the US Enviromental Protection Agency for Cr is 350-times the upper limit of the Estimated Safe and Adequate Daily Dietary Intake (ESADDI) of 3.85 mmol (200 ug/day). The Reference Dose (R/D) is defined as „an estimate of a daily exposure to the human population, including sensitive subgroups, that is likely to be without an appreciable risk of deleterious effect over a lifetime”. Anderson et al (1997) demonstrated no evidence of toxicity or toxic effects in any of the human studies involving chromium supplementation.

V. Therapeutic Values of Cinula® On the basis of the above short description, the FDC Cinula® capsule which contains 250mg Cinnulin PF (the real water soluble doubly linked polyphenolic type-A polymers = PTAP), 300mg ALA, and100mcq Vit. B12 is the rationale and appropriate composition for patients with obesity, the MetS, pre diabetes, and T2DM. The Cinula® can be administered before meal in a dose of 1-3 capsules / tablets per day. The 6 (six) properties previously mentioned plus its effects to delay GER, Cinula® can lead to a lower postprandial blood glucose level (in addition to decreased FBG).