α-Cyclodextrin and Metabolic Disorders

by Stephen F. Olmstead, MD

The Impact of Metabolic Disorders

Obesity and type 2 diabetes mellitus are pandemic metabolic disorders commonly complicated by cardiovascular disease (CVD).^1,2 Obesity is projected to affect over 40% of Americans in 2015.³ From 1980 to 2010 the prevalence of diabetes nearly quadrupled, rising from 5.5 million persons to 21.1 million.² Worldwide, diabetes is expected to affect 592 million people by the year 2035, nearly 7% of the world’s population. The conjunction of central or visceral obesity with insulin resistance, high blood pressure, elevated triglycerides, reduced high density lipoprotein (HDL) cholesterol levels, and a pro-inflammatory, prothrombotic milieu is termed metabolic syndrome.⁴ People with metabolic syndrome have double the risk of developing CVD.⁵ The risk of heart attack is increased by 3- to 4-fold, while the risk of stroke is 2- to 4-fold greater in metabolic syndrome than for people without the diagnosis.⁴ When people with metabolic syndrome suffer a myocardial infarction or stroke, they are twice as likely to die.⁵ Metabolic disorders represent major modifiable risk factors for CVD as well as the myriad of other associated complicating diseases.

Standard Approaches to Metabolic Disorders

Obesity is clearly driving the increased rates of metabolic disorders.¹ Although obesity is increasingly appreciated as a complex systemic inflammatory metabolic disease, excessive consumption of energy-dense foods and a sedentary lifestyle are at its core. Consequently, approaches to metabolic disorders have focused on weight loss primarily through diet and exercise.⁶ While the merits of low-carbohydrate diets versus low-fat diets are contentiously debated, a daily reduction in calorie intake is essential to successful weight loss.^1,7 The daily energy deficit should be about 500 calories to sustain consistent weight reduction. Even modest weight loss delivers numerous metabolic health benefits such as reduced blood pressure, improved insulin sensitivity, decreased triglyceride levels, and increased HDL-cholesterol.⁸ Exercise plays a crucial role in initial weight loss and healthy weight maintenance.⁹ There is evidence exercise promotes visceral fat loss.¹⁰ Even without weight loss, exercise can improve insulin sensitivity in people who had been sedentary.¹¹

Weight Loss: Simple in Theory, Difficult in Practice

Although the prescription of diet and exercise for metabolic disorders is simple and straightforward, in clinical practice it is challenging for people to maintain a diet and exercise regimen. Even when people are diligent, modest weight loss is the best expected outcome from participation in a structured diet program.^7,12 Commitment and adherence to a change in diet and lifestyle are often insurmountable barriers to involvement in a weight-loss program.¹³ Even when initial weight loss is accomplished, long-term maintenance of the more healthful weight has proved to be a major challenge.⁷ Clearly, additional interventions are needed to make diet and exercise more effective in metabolic disorders. One dietary intervention accepted as beneficial in metabolic disorders is the increased intake of soluble dietary fiber, usually as oat bran, pectin, or psyllium.¹⁴ The soluble fiber needs to be viscous to confer metabolic benefits.¹⁵ A viscous fiber forms a gel on hydration. While recommending the increased intake of foods containing high amounts of fiber is standard advice, a supplemental soluble fiber such as psyllium in daily doses of 10 to 25 grams is generally needed to achieve improvements in insulin sensitivity, lipid levels, and body mass index. These doses are often not palatable or well tolerated. A viscous soluble dietary fiber called α-cyclodextrin, offering significant potential benefits to people with metabolic disorders, is now available as a dietary supplement.

α-Cyclodextrin

Cyclodextrins are naturally occurring oligosaccharides consisting of D-glucose molecules linked end-to-end by α-1,4 glycosidic bonds to form a circular structure.¹⁶ The molecular structure of cyclodextrins resembles a doughnut or truncated cone. Cyclodextrins derive from the action of the bacterial enzyme cyclodextrin glucosyltransferase (EC 2.4.1.19) on food starch.¹⁷ Cyclodextrins are designated by a miniscule Greek letter according to the number of D-glucose molecules linked in a ring. α-cyclodextrin contains 6 D-glucose molecules, β-cyclodextrin contains 7, and γ-cyclodextrin contains 8. Of these three naturally occurring cyclodextrins, the greatest interest over the years has been in β-cyclodextrin, as it has been relatively easy and inexpensive to produce.¹⁶ However, α-cyclodextrin offers the greatest potential in metabolic disorders by virtue of three essential properties: It is highly water soluble, its glycosidic bonds are resistant to hydrolysis by human salivary and pancreatic α-amylase, and it can complex with dietary fat.¹⁶

α-Cyclodextrin and Dietary Fat

The truncated conelike structure of α-cyclodextrin was first described in 1942.¹⁸ X-ray crystallography disclosed that the primary C6 hydroxyl groups on the D-glucose molecules are located on the smaller outer ring of the truncated cone, while the secondary C2 and C3 hydroxyl groups are located on the larger outer ring. This creates a highly polar ring exterior that facilitates water solubility. On the interior of the ring are found apolar hydrogens and etherlike oxygens that result in a relatively hydrophobic space within the truncated cone. This hydrophobic space allows α-cyclodextrin to complex with lipophilic molecules such as the bi- and triglycerides that constitute most dietary fat. Due to its high water solubility and resistance to α-amylase, an ingested dose of α-cyclodextrin can pass intact and in solution through the stomach into the small intestine where between 2% and 3% is absorbed.¹⁹ When ingested with dietary fat, α-cyclodextrin forms microemulsions with bi- and triglycerides.²⁰ α-cyclodextrin interferes with fat absorption by preventing the hydrolysis of bi- and triglycerides into free fatty acids and glycerol. In a rodent feeding study and in vitro experiment, α-cyclodextrin has been found to complex with dietary fat in approximately a 1:9 ratio.²⁰ Given size constraints, each α-cyclodextrin molecule cannot accommodate more than 1 fatty acid tail within its interior space, so α-cyclodextrin molecules must combine to form microemulsions with hydrophobic interiors composed of bi- and triglycerides with α-cyclodextrin-fatty acid complexes on the exterior. The α-cyclodextrin-fat complexes are resistant to digestion and pass through the small intestines intact into the colon. α-cyclodextrin is clearly fermented by the colon microbiota. Evidence from a rat study in which animals were fed a diet containing 5% w/w α-cyclodextrin as well as 7% soybean oil suggested that the α-cyclodextrin-fat complex was metabolized resulting in increased cecal concentrations of organic acids, especially the short-chain fatty acids acetate and propionate.²² In other studies involving differing doses of α-cyclodextrin and higher amounts of dietary fat, α-cyclodextrin has been shown to increase fecal fat indicating incomplete microbial fat digestion.^20,23

α-Cyclodextrin and Body Weight

Clinical studies demonstrate α-cyclodextrin’s beneficial effects on weight management. In one trial, 66 obese people with diabetes mellitus were randomized to take 2 grams of α-cyclodextrin as FBCx or placebo with every fat-containing meal and followed for 3 months.²⁴ All subjects had been gaining an average of 2.2 ± 0.88 lbs per month before beginning the study. People who received α-cyclodextrin stabilized their weight while those on placebo continued to gain weight. When weight change was normalized for dietary energy intake, people receiving α-cyclodextrin lost weight. The most weight loss occurred in people who reduced energy intake while consuming α-cyclodextrin. α-cyclodextrin had less impact on weight in diabetics taking insulin, although it still reduced daily energy intake by 237 calories as compared with 522 calories for noninsulin users. In a double-blind, crossover study involving 41 healthy but overweight adults, α-cyclodextrin alone facilitated significant weight loss over 2 months without diet or exercise.²⁶ Although none of the participants reduced their caloric intake, people receiving α-cyclodextrin lost on average a little less than 1 lb during the study compared with controls. Animal studies suggest that prevention of dietary fat absorption is the principal mechanism for preventing weight gain and promoting weight loss. In a rat model of diet-induced obesity, α-cyclodextrin with a high-fat diet led to a significant 22% reduction in body fat compared with control animals fed the high-fat diet alone.²⁰ In the same animal study, α-cyclodextrin significantly reduced leptin levels. Leptin is a satiety hormone made by adipocytes that normally inhibits hunger.²⁶ Leptin levels paradoxically rise with obesity due to leptin resistance or tolerance.

α-Cyclodextrin and Dyslipidemia

The salutary effect of α-cyclodextrin on serum lipids fundamentally depends on whether dyslipidemia is present. In the clinical trial of people with diabetes, α-cyclodextrin significantly lowered cholesterol levels providing the subjects had hypertriglyceridemia on entry into the study.²⁴ The decrease in total cholesterol was due to the reduction in low density lipoprotein (LDL) cholesterol. No change in HDL-cholesterol was observed. Fasting serum triglycerides were reduced in people not using insulin, although the change did not attain statistical significance. In the study of healthy but overweight adults, α-cyclodextrin significantly lowered total cholesterol and LDL-cholesterol levels in subjects entering the study with hypercholesterolemia and hypertriglyceridemia.²⁵ It also effectively lowered circulating apolipoprotein B, a lipoprotein strongly associated with an increased risk of atherosclerotic vascular plaque and coronary heart disease. In a study of 34 healthy individuals, 2 grams of α-cyclodextrin significantly lower postprandial triglycerides following a standardized meal.²⁸ The magnitude of the postprandial triglyceride reduction was strongly dependent on fasting triglyceride levels. Elevated nonfasting triglycerides are an independent risk factor for ischemic heart disease and death. Animal studies suggest that α-cyclodextrin may have a greater binding affinity for saturated fats and trans fatty acids.²³ In the LDL receptor knock-out mouse model of atherosclerosis, α-cyclodextrin significantly lowered plasma total cholesterol, free cholesterol, cholesterol esters, and phospholipid levels.³¹ The mechanism whereby α-cyclodextrin lowers cholesterol levels is unclear. Cholesterol is too large to be complexed by α-cyclodextrin. However, α-cyclodextrin has been shown to complex lecithin in bile salt micelles, thereby decreasing the bile salt micellar solubility of cholesterol, which reduces absorption.³² Another potential mechanism is that α-cyclodextrin’s properties as a prebiotic alter cholesterol’s metabolism through increased short-chain fatty acid production.^22,32

α-Cyclodextrin and Insulin Sensitivity

α-cyclodextrin effects a dose-dependent improvement in glucose tolerance and insulin sensitivity. When taken by healthy people together with 50 grams of digestible starch, 5- and 10-gram doses reduce the incremental area under the curve (iAUC) for postprandial glucose.³³ A 2-gram dose also flattened the glucose iAUC, although there were too few subjects to reach statistical significance. Studies show that cyclodextrins competitively bind and inhibit pancreatic α-amylase, indicating a mechanism whereby α-cyclodextrin can reduce postprandial glucose loads.³⁴ Among healthy but overweight people, α-cyclodextrin decreased insulin levels by nearly 9.5%, consistent with improved insulin sensitivity.²⁵ In people with obesity and diabetes, α-cyclodextrin increases adiponectin levels, especially in those not using insulin.²⁴ Higher adiponectin levels favorably affect insulin tolerance, glucose regulation, and weight reduction.²⁶

Conclusion

α-cyclodextrin is a naturally occurring soluble fiber first described in 1891.¹⁶ Only recently are its potentially beneficial effects in the setting of metabolic disorders becoming better appreciated. It resists digestion by α-amylase. Its steric conformation allows it to complex with the acyl tails of fatty acids, allowing the formation of microemulsions of dietary fat. α-cyclodextrin can reduce fat absorption and appears to prevent weight gain and promote weight loss. In people with dyslipidemia, α-cyclodextrin reduces cholesterol and LDL-cholesterol levels, and blunts the rise in postprandial triglycerides. It favorably affects insulin sensitivity in a dose-dependent manner. α-cyclodextrin offers beneficial nutritional support in the setting of metabolic disorders.

Notes

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Stephen F. Olmstead, MD, is chief science officer at ProThera Inc., where he oversees technical and scientific services. He is an internationally recognized biofilm expert, and his current research focus is on the use of enzymes and chelating agents to disrupt pathogenic gastrointestinal and systemic biofilms. Dr. Olmstead authors nationally published scientific articles and technical summaries and hosts webinars designed for health-care providers. Dr. Olmstead graduated from the University of New Mexico with distinction in biology and chemistry. He attended the University of New Mexico School of Medicine and trained at Harvard Medical School, Massachusetts General Hospital. He is board certified in both internal medicine and cardiovascular diseases.