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Vladimir Badmaev, MD PhD
Regulation of Glucose in the body
Glucose is one of the single most important life sustaining nutrients in the body. Consider that a sudden drop in blood sugar (glucose) levels, technically referred to as hypoglycemia, can cause a person to pass out. If the blood sugar levels are not normalized within a relatively short time, irreversible damage to the central nervous system can occur. This critical role of glucose in sustaining vital signs is obvious, in chronic glucose starvation of tissues that occurs in diabetes. Typically, a diabetic patient may complain of chronic tiredness, lack of energy and feeling of persistent physical weakness even after resting. This is due to faulty delivery of glucose to the brain and body cells, which results in diabetics literally feeling drained of energy like people deprived of daily meals.
Brain cells, red blood cells and muscle especially during exercise require a continuous supply of glucose in order to fuel metabolic processes, especially bioenergetic processes. Because glucose is essential for the organism to properly function, its availability for the body is secured by several mechanisms. The primary source of glucose is from dietary carbohydrates (sugars) which are predominantly polymers of hexoses (six carbon containing sugars), of which the most important is glucose. The normal fasting level of glucose in peripheral venous blood is 70-110 mg/dl. In arterial blood, the glucose level is 15-30 mg/dl higher than in venous blood.
Once glucose enters the cells, pumped there from the blood by the hormone insulin, it is metabolized in two principal directions: (1) utilization for energy and building functional and structural proteins in the body (glycoproteins) or (2) storage in form of glycogen (polymer of glucose) to secure the availability of glucose at times of its immediate need. The process of glycogen formation from glucose is called glycogenesis, and glycogen breakdown to release glucose for metabolic needs is called glycogenolysis. Glycogen is present in most body tissues, but the major supplies are in the liver and skeletal muscle. The breakdown of glucose to pyruvic acid or lactic acid (or both) is called glycolysis. Liver glycogen can meet the organism’s needs for glucose to sustain vital tissues only for 10 to 18 hours without dietary carbohydrate. That is why the supply of glucose is secured by the next mechanism in line which derives glucose from other body nutrients and biomolecules like amino acids, glycerol, pyruvate and lactate. This process of converting other nutrients to glucose is called gluconeogenesis. Gluconeogenesis is controlled primarily by the circulating levels of glucagon, a pancreatic hormone which opposes and complements the action of insulin. The inadequate supply of cells with glucose, as occurs in untreated diabetes, leads to increased oxidation of fatty acids in the liver cells’ mitochondria and the formation of ketone bodies. The ketone bodies are utilized as an alternative source of energy by the body starving for glucose, especially the brain, red blood cells and muscles. Excess of ketone bodies leads to a profound diabetic pathology.
Diabetes, a disease aggravated by inactive life style and unbalanced nutrition
Diabetes is quickly becoming one of the most debilitating chronic diseases of modern society (the name is derived from the Greek word “diabainein” which means “to pass through” , since sugar is being passed in the urine of diabetics). Two main types of diabetes, Type I and Type II, are distinguished in literature. Type I, also called juvenile diabetes or insulin dependent diabetes mellitus (IDDM), occurs due to the lack of insulin production by the pancreas; while Type II, also known as adult onset or non-insulin dependent diabetes mellitus (NIDDM), is attributed to the loss of insulin receptors in the body tissues. Diabetes is listed as the leading cause of non-congenital blindness and kidney failure among adults 20 to 70 years of age. Diabetes also leads to accelerated atherosclerosis, which increases one’s risk for heart disease, stroke and peripheral vascular disease (PVD). The latter condition commonly leads to gangrenous changes of the lower extremities in diabetics, which necessitates surgical amputation in some cases.
In diabetes, the system of body glucose regulation is confused by the fact that circulating glucose is elevated while the tissue is depleted of glucose due to malfunctioning of glucose transportation to the cells. In this situation, paradoxically, the mechanisms to increase glucose are activated which lead to spinning wheel phenomenon, i.e. blood glucose is further increased, glycogen stores are depleted and other body nutrients are broken down to be converted into glucose.
In diabetes, an excess of circulating glucose which cannot be utilized properly by the tissues triggers a broad range of pathology, including:
1. The continuously elevated blood glucose fuels the citric acid (Krebs) cycle which provides building blocks for fatty acids synthesis. This process directly contributes to elevated blood cholesterol (especially an increase in blood triglycerides, nicknamed “ugly” cholesterol) and obesity which often accompanies diabetes of the NIDDM type, as well as wasting lean body mass (lean body mass equals total body weight minus body fat).
2. Excess, unutilized glucose leads to the abnormal process of protein glycosylation (i.e. carbonyl group of glucose reacts with amino groups in target protein). These glycation reaction products accumulate in tissues not only in diabetes but also in individuals of advanced age and with renal failure. There is emerging evidence that these compounds may play a role in vascular pathology (accelerated atherosclerosis), neurological (diabetic neuropathy), ocular (cataract formation) and renal complications (diabetic renal failure) associated with diabetes and aging.
3. Oxidative damage to DNA has been well documented in cells isolated from subjects with diabetes. Research indicates that activation of the insulin receptor by insulin or an insulin equivalent is necessary to induce cells to produce their own DNA repair enzyme. When insulin is lacking or the insulin receptor is defective the repair enzyme is not produced. Thus the damaged DNA is not repaired which may lead to premature cell aging and death.
4. Free radical pathology in diabetes activates all reserve systems in the body to repair DNA damage. This chain of events may deplete tissue stores of nicotinamide adenine dinucleotide (NAD), which participates in activation of tissue repair enzymes. Depletion of NAD leads to premature cell death. In accelerated atherosclerosis in diabetes manifested by stroke or heart attack depletion of NAD is very prominent.
5. Clinical symptoms, excessive thirst, hunger and excessive urination, are common in diabetics. The excess glucose and ketone bodies in the blood act as a diuretic; excessive diuresis contributes to thirst; and glucose-starved tissue may trigger an excessive appetite for food.
6. Premature aging due to wasting of body nutrients, extensive damage to skin, internal organs (glycation reaction) and biomolecules (gylycosylation or damage of hemoglobin), rapid deterioration of cardiovascular system (so called “small vessel” disease), and damage to the autonomous and peripheral nervous systems (neuropathy).
Nutritional control of diabetes
One of the mainstay in the prevention and management of diabetes is nutritional regimen. This approach is especially useful to improve glucose metabolism, lower elevated LDL (“bad cholesterol”) and decrease the body weight. The nutritional approach is prior to and in addition to drug therapy. The most widely used dietary program to lower blood cholesterol is the Step 1 diet developed by the American Heart Association (AHA). It contains no more than 30 % of calories from fat, less than 10% of calories from saturated fatty acids, less than 300 mg of cholesterol, 50-60% of calories from carbohydrates and 10-20% of calories from protein. The person planning to follow this diet should receive instructions from a dietitian or qualified professional. The Step 1 diet usually produces a modest decrease in “bad cholesterol” of approximately 10%.
Patients who could not reach their cholesterol lowering goals or those with established cardiovascular disease should be instructed to follow Step 2 diet. This diet contains no more than 30% of calories from fat, less than 7 % of calories from saturated fatty acids and less than 200 mg of cholesterol per day (The other parameters are identical to the Step 1 diet). Patients with elevated levels of triglycerides, are recommended to restrict simple sugar intake. The threshold for initiation of dietary therapy includes a total cholesterol 240 mg/dl and LDL 160 mg/dl with 0 or 1 risk factor for cardiovascular disease, or 200 mg/dl and 130 mg/dl with more than 2 risk factors for cardiovascular disease, or 160 mg/dl and 100 mg/dl with known cardiovascular disease.
Dietary management of hyperlipidemia associated with Type 2 diabetes may require a customized approach to improve insulin sensitivity while lowering blood lipids. Studies show that a diet high in monounsaturated fats significantly improves insulin sensitivity compared to a diet high in saturated fat. However, the beneficial effect of monounsaturated fat disappears when the total fat intake exceeds 38% of total energy. Dietary carbohydrate intake should be carefully monitored to avoid the detrimental effects of a high-carbohydrate diet on plasma glucose/insulin and the triglyceride/HDL ratio. Carbohydrate foods with a high glycemic index should be avoided with preference given to fiber-rich, low-glycemic-index foods. In general, studies indicate that high-fat diets containing a higher proportion of unsaturated fat result in better control of glucose metabolism than high-carbohydrate diets. Studies also indicate that a low-carbohydrate, high protein hypoenergetic diet may be the diet composition of choice for a weight-reducing regimen in obese, hyperinsulinemic subjects.
The newly emerging dietary considerations in reducing cardiovascular risk deal with mineral status and mineral supplementation. Among adolescents at risk for hypertension, blood pressure was lower in those with higher intakes of a combination of nutrients, including potassium, calcium, magnesium, and vitamins. Intracellular magnesium is an important modulator of heart muscle function. Hypomagnesemia is common in patients with cardiovascular disease and may contribute significantly to cardiovascular morbidity and mortality. A positive association has been found for both men and women concerning supplemental zinc intake and improved lipid profile. Zinc may also be an important dietary consideration among patients with diabetes since they are often zinc deficient. Zinc deficiency may contribute to cardiovascular risk by increasing the detrimental effects of certain inflammatory compounds, such as cytokines, (e.g. TNF), on endothelial cells lining blood vessels. Some findings concerning the role of selenium in modifying the body’s homeostasis relate to its effect on blood coagulation and its potential as an anti-arrhythmic agent – both mechanisms play a role in prevention of cardiovascular disease risks. Selenium deficiency in rats significantly decreased aortic prostacyclin synthesis (an anti blood clotting compound) but did not affect the platelet thromboxane synthesis (a compound increasing blood clotting). It has been postulated that the unusually high mortality rate from cardiovascular disease in southeastern Georgia may, in part, be due to selenium deficiency.
Gymnema Sylvestre: a safe approach to glycemic control
Diabetes has been recognized since ancient times, and there are worthy botanical therapies found in indigenous medical traditions like Ayurveda, an alternative medical practice developed in India.
Gymnema sylvestre or Asclepias germinata (fam. Asclepiadaceae) is probably one of the most researched botanical ingredients in the management of diabetes. The extraction of Gymnema sylvestre compounds, gymnemic acids, relevant to its antidiabetic properties has been scientifically known since the publication by Hooper in 1887 (Pharm J Trans 17, 367(1886/87)). Since then numerous gymnemic acids were isolated from Gymnema sylvestre extract by various researchers (Yackzan, 1966; Stocklin,1967; Sinsheimer et al. 1968; Karihara 1969; Dateo, Long 1973; Chakravarti, Debenath 1980; Liu et al. 1992). Gymnemic acids are saponins with a triterpenoid structure; gymnemagenin is an aglycone of gymnemic acids. Another important compound isolated from the Gymnema plant is gurmarin, a 35-residue polypeptide. Gurmarin is a compound that can selectively inhibit the neural response to sweet taste when taken orally (Fletcher, JI 1999). This compound in a dose of 10 mcg/ml significantly depressed (40-50%) experimental animals’ taste responses to sugars (sucrose, fructose, lactose, and maltose) and saccharin sodium (Harada, S 2000).
Several preclinical and clinical studies established a water soluble extract of Gymnema sylvestre as a potential alternative approach to diabetes treatment. The extract standardized for 25% gymnemic acids has been clinically tested in controlling hyperglycemia and related pathology in patients presenting with Type I and Type II diabetes (Shanmugasundaram, ERB et al. 1990 and Baskaran, K. et al. 1990). The extract was administered daily in a dose of 400 mg to 27 Type I diabetics for up to 30 months along with daily insulin injections. These patients were compared to 37 controls who received insulin therapy alone. The combined therapy, compared to the insulin alone regimen, resulted in significant reductions in the levels of blood glucose, glycosylated hemoglobin, glycosylated plasma proteins and serum lipids (triglycerides and LDL cholesterol). In addition, the patients’ insulin dose was reduced to nearly half of the original amount.
The 400 mg/day of 25% was investigated in 22 Type 2 diabetic patients who received the extract for 18-20 months as a supplement to the conventional oral antidiabetic drugs. All patients showed a significant reduction in blood glucose, all were able to gradually decrease conventional drug dose, and five of the study group were able to discontinue drug treatment to maintain their blood glucose homeostasis with the gymnemic acids alone. In addition, plasma levels of glycosylated hemoglobin and glycosylated proteins were decreased as a result of gymnemic acids administration.
Animal studies indicate that gymnemic acids may be involved in regeneration of damaged pancreatic islets responsible for manufacturing insulin (Shanmugasundaram, ERB et al. 1990, and Okabayashi, Y 1990, Sugihara, Y 2000). Two water soluble extracts of Gymnema sylvestre standardized for different fractions of gymnemic acids, were tested in streptozotocin (chemical damaging pancreatic islets) treated rats for their effects on blood glucose homeostasis. The fasting blood glucose and the insulin levels in experimental animals were normalized after 60 days of both fractions oral administration. The authors of the study concluded that the therapeutic results were likely due to repair/regeneration of the endocrine pancreas with the Gymnema extracts. The effects of gymnemic acids on insulin secretion from rat islets of Langerhans were evaluated in vitro. The results of this study confirm the stimulatory effects of Gymnema sylvestre on insulin release from the pancreatic cells, and indicate that gymnemic acids may act by increasing cell permeability which facilitates insulin release(Persuad, SJ 1999).
The effects of Gymnema sylvestre extract on glycogen in rats fed normal and high-sugar diets was evaluated. The extract did not alter the hepatic glycogen content in normal rats, while it significantly lowered the glycogen content of the tissues in high-sugar diet rats. This effect was further potentiated when both exogenous insulin and leaf extract was administered (Chattopadhyay RR, 1998). The extracts of Gymnema leaves administered to guinea pig suppressed intestinal smooth muscle contraction, decreased oxygen consumption, inhibited glucose evoked-transmural potential, and prevented blood glucose level increase. The authors concluded that Gymnema extract interferes with the intestinal glucose absorption process (Shimizu, K 1997).
The clinically know cholesterol lowering effect of Gymnema sylvestre extract was evaluated in rats (Nakamura, Y 1999). The fecal excretion of cholesterol, total neutral steroids and total bile acids was significantly increased in rats who received the Gymnema extract diet compared to the control group, and these results correlated positively with fecal gymnemagenin levels. Another study evaluated the effects of gymnemic acid on oleic acid absorption in rats (Wang, LF 1998). The results showed that the gymnemic acid inhibited the absorption of oleic acid, this inhibition was dose dependent and reversible.
In summary, supplementation with Gymnema sylvestre extract has a potential to improve the health of diabetic patients, especially those who have a healthy active lifestyle and eat a sensible diet. The overall objective of nutraceutical/nutritional support in diabetes should focus on weight and cholesterol management, increase in lean/fat body mass proportions, and eventually improvement of glucose homeostasis.