Independent Research Document
Glycemic Research Institute

www.Glycemic.com
www.CephalicResearch.com

2007-2009

State-of-the-Art biomedical research has identified the key factors related to obesity, weight management, insulin resistance, and type 2 diabetes in humans. The primary factors are:

EVOLUTIONARY INFLUENCES

Obesity is obviously a consequence of increased food intake, driven by palatability and marketing, while the over-riding endocrine and genetic factors are silent partners in the obesity epidemic.

Anthropological-driven hormonal factors, such as Serotonin and Testosterone, stimulate humans to “eat all the time" and in great variety, thus persons genetically destined to become obese may eat more often, more rapidly, and in larger quantity before reaching satiety.

The role of hard-wired food-related mechanisms are currently being explored, such as Agouti-related protein (AgRP), a hypothalamic peptide involved in the regulation of feeding.

ADIPOSE FAT-STIMULATION VIA SWEETENERS

One of the major evolutionary tricks for survival is the desire for fattening foods. Without sufficient body fat levels in the female, the human species cannot procreate, and becomes extinct. This is observed in anorexics, in which low body fat results in cessation of menses and thus the inability to produce children. In males, low body fat levels do not prevent procreation.

Ergo, the female of the human species is hard-wired to create and hold higher body fat levels. In terms of survival of the species, the fatter, the better.

This is not a preferable advantage in a society of abundant and fattening foods. But, the brain is unaware of this fact, and cannot fathom that there are grocery stores and fast food. It could take hundreds of years before humans evolve to the point that the brain understands that there is food-a-plenty.

SWEETENERS THAT TAKE ADVANTAGE OF ANTHROPOLOGY

Sweeteners, both natural and synthetic, can stimulate adipose tissue fat-storage, primarily in belly-fat. In the female, procreation requires adequate levels of adipose tissue abdominal fat (belly fat). This area-specific fat helps insure a healthy baby.

The biochemical mechanisms that separate natural and synthetic sweeteners vary, but the result is the same, weight gain, more and larger fat cells, insulin resistance, and increase in incidence of type 2 diabetes.

Natural sweeteners can cause fat-cell-stimulation as can artificial sweeteners. Neither are exempt from contributing to human obesity and diabetes.

Sweeteners that contain -0- sugars, -0- fat, and -0- carbohydrates can still trigger abdominal obesity (belly fat) and parallel increases in type 2 diabetes and insulin resistance.

The culprits, in both natural and artificial sweeteners, can be identified as:

In foods and beverages, some sweeteners are not labeled as sugars, but act like sugars, such as Maltodextrins. Though the food/beverage label may state -0- sugars, there may be enough non-labeled sugars to cause huge elevations in blood glucose, insulin, Cephalic, and LPL fat-storage.

Foods, snacks, and beverages that contain fat-storing sweeteners, such as sugar (sucrose) and/or glucose, leads to dopaminergic and endorphin brain reward signals, with gastrointestinal satiety mechanisms leading to negative feedback from the gut via hormonal output.

PROTOCOLS

The effects of sweet taste and energy content on fat-stimulating responses can be quantified in Human In Vivo clinical trials. This requires the implementation of specific protocols that have been designed to measure the concomitant changes in blood glucose, insulin concentrations, and other perimeters, as related to oral ingestion of various sugars and sweeteners.

In the natural sugars and carbohydrates arena, sucrose, glucose, and maltodextrins are the most commonly used ingredient in foods and beverages.

Identifying fat-storing perimeters in artificial sweeteners is more complicated, and requires Cephalic testing. Combinations of natural sugars and artificial sweeteners mandates bi-and tri-level clinical trials in humans designed to track known fat-storage mechanisms and bio-markers.

Current protocols in quantifying fat-storage mechanisms in humans include glycemic indexing, Cephalic testing, randomized crossover design trial with functional magnetic resonance imaging, gastric lipase secretion, changes in gastrointestinal transit activity, pancreatic exocrine response, and gut hormonal response.

In studies with six different olfactory stimuli, the medial orbitofrontal cortex represents pleasant taste experiences, while the lateral orbitofrontal cortex represents unpleasant taste stimuli. Specific portions of the brain build associations between different food-related stimuli.

In the design of food and beverages, manufacturers have addressed more than visual aspects. Taste, sweetness, olfactory, and cognitive inputs have been intensively used to advantage by food manufacturers, thus overriding evolutionarily developed satiety signals.

During clinical trials, quantification of fat-storage factors related to a specific sugar, or combination of sugars and sweeteners (1), can be accurately determined utilizing controls against a specific percent of sugar or carbohydrate solution dissolved in water (Test Agent).

If the sugar/sweetener is present in a food or beverage, Comparative Analysis Trials can used to compare the biochemical value of a sugar/sweetener with a control that does not contain any sugars or sweeteners (1).

Cephalic testing (CPIR) requires highly sophisticated methodologies and equipment designed to track brain-insulin-signaling with miniscule half-lives (1).

IDENTIFYING BIOCHEMICAL CULPRITS

Prolonged and significant signal decrease in the upper hypothalamus (P < 0.05) can be observed in whereas control agent will exhibit no such effect.

Ingested Test Agents that increase glycemic perimeters, blood glucose and/or insulin concentrations, and/or trigger an early rise in insulin concentrations and/or Cephalic Phase Insulin Response (CPIR) are considered culprits in weight gain, obesity, type 2 diabetes, and insulin resistance.

PATHOLOGY of SUCROSE & GLUCOSE FAT-STORAGE

Aside from stimulating glycemic and insulinogenic perimeters, high glycemic sugars such as sucrose and glucose, can stimulate intense fat-storage, reactive hypoglycemia, as well as Cephalic Response via the brain.

There is a prolonged dose-dependent decrease in the blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) signal in the hypothalamus a few minutes after the ingestion of a glucose solution.

BOLD functional MRI (fMRI) measures changes in neuronal activity levels based on the associated changes in the local concentrations of oxygenated and deoxygenated hemoglobin.

Hypothalamic response to sweet taste and energy content of the sucrose/glucose mix and concomitant changes in blood glucose and insulin concentrations: Sucrose/glucose ingestion resulted in a prolonged signal decrease in the upper hypothalamus, with a negative early rise in plasma insulin.

Parallel observations have been identified in which researchers found a preeminent role of glucose in triggering cephalic phase insulin release (CPIR). Early decrease in the hypothalamic signal, is observed post-glucose ingestion, and is associated with CPIR.

Further, glucose is associated with an early rise in insulin concentration, and glucose triggers a decrease in fMRI signal in the upper hypothalamus. The additional decrease in fMRI signal is associated with a rise in insulin concentration.

DIABETIC INSULIN PROFILES

Use of sucrose/glucose mixtures and or glucose without sucrose, leads to a diabetic insulin profile as associated with a higher glucose peak and a prolonged duration of hyperglycemia.

Insulin secretion can occur in a biphasic manner depending on the type and magnitude of the glucose stimulus (dose/level). Chronic hyperinsulinemia can lead to -cell exhaustion, causing down-regulation of the insulin receptor and increasing insulin resistance, which can produce negative consequences on the vascular endothelium.

The magnitude of the first phase of CPIR occurs in response to a single-step glucose stimulus increases with increasing doses of glucose. The amount of insulin released during this phase is a sigmoidal function of glucose concentration (with a half-maximum for glucose of 135 mg/dl). If ingestion continues in short intervals, this first-phase insulin response is inhibited; in contrast, if longer time intervals are used, enhancement of the first-phase insulin response is observed at the second stimulation.

BIPHASIC INSULIN RESPONSE

First phase of CPIR occurs instantaneously after ingestion of a Cephalic agent, while the 2nd CPIR phase can last for a few hours, if the -cell is continuously exposed to glucose.

Source: Glycemic Research Institute/Cephalic Research Institute

DEFINING LIPOGENESIS (FAT-STORAGE)

Lipogenesis is the process that converts excess dietary carbohydrates into fat for storage as a source of long-term energy (adipogenesis). The deposition of fat and/or the conversion of carbohydrate or protein to fat, in this case facilitated by sucrose/glucose ingestion, changes insulin concentrations post-prandially, and correlates positively with a change in hepatic lipogenesis resulting in adipose tissue fat-storage.
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IN CONCLUSION

Foods and beverages with zero sugars and zero calories can trigger fat-storage and insulin release. Swallowing the food or beverage is obsolete to the Cephalic Response.

Cephalic phase hormonal release occurs through activation of vagal-efferent fibers in response to food-related sensory stimuli. Tasting, chewing and expectorating food elicits hormonal release prior to nutrient absorption.

With properly designed clinical trials, the physiological consequences of ingesting various sugars, carbohydrates, and sweeteners can be identified and quantified.

The resulting data is an educational tool for the public fighting an obesity and diabetic epidemic, as well as a metabolic map for food and beverage manufacturers.

REFERENCES

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Scientific Data
Human In Vivo Clinical Trials

2008 - 2009

The term Anti-Carbohydrate ™ has been assigned to Sweet Infused Fruits™ due to their unique ability to mitigate, block, and prevent the typical metabolic reaction as related to every known carbohydrate, and as opposed to all other carbohydrates.

Sweet Infused Fruits ™ have been shown to be capable of reversing the known and proven responses to high glycemic foods, with benefits in post-prandial blood glucose, insulin, and adipose tissue fat-storage via Lipoprotein Lipase.

Small doses of Sweet Infused Fruits ™ (7-8 g) consumed 30 or 60 minutes prior to consuming a high glycemic index (50 g/carb), starchy food decreases the glycemic response compared with either immediate or no Sweet Infused Fruits ™ treatments.

Further, this same dose of Sweet Infused Fruits ™ (7-8 g) reduces the glycemic response to a very large volume of an extremely high glycemic (75 g/carb beverage, soda, or sports drink.

Sweet Infused Fruits ™, unlike high glycemic sweeteners and sugars, does not stimulate insulin secretion from pancreatic ß-cells. Physiological sensing of plasma glucose is primarily elucidated at the level of the pancreatic ß-cell.

These findings provide practical applications as the small amount of Sweet Infused Fruits ™ required for this response can easily be supplied as an adjunct to the diet.

CLINICAL TRIALS # 1 - 4
Sweet Infused Fruits ™ acutely and significantly mitigates blood glucose and glycemic responses, and fat-storage properties of oral ingestion of ice cream in humans.

CLINICAL TRIAL # 5
Sweet Infused Fruits ™: Mitigation of adipose tissue fat-storage, blood glucose and glycemic responses, Lipoprotein Lipase, and insulin resistance in reaction to oral ingestion of chocolate candy in humans.

CLINICAL TRIAL # 6
Sweet Infused Fruits ™: Mitigation of the diabetic, glycemic and metabolic responses in humans associated with oral ingestion of Glucosamine, a known diabetic-risk-agent.

INSULIN & PRE-DIABETES IN CHILDREN:

INSULIN RESISTANCE

In 2008, renowned Pediatrician, Dr. William Sears*, stated “Carbs are Killing our Children.” Dr. Sears describes Pre-Diabetes in children as Insulin Resistance, and has seen “narrowing of the arteries in children as young as 3-years old, with insulin levels of 38.

Normal insulin levels range from 11-19. The upper limit insulin level is 29. In children who are Pre-Diabetic, insulin levels reach as high as 38.

The Pre-Diabetic stage is the precursor to full blown type 2 diabetes and personifies Insulin Resistance. During this stage of insulin imbalance, the body has lost the ability to process sugar and high glycemic carbohydrates, and there is not enough insulin to help the sugar get into the cells and use it as energy. When this occurs, the sugar/carbohydrate goes into storage (fat cells) instead of being utilized as an energy fuel.

Repeated consumption of foods and beverages that stimulate this response leads to obesity and type 2 diabetes in children and adults. The obesity and Insulin Resistance epidemic in children keeps escalating with no end in sight. As long as children continue to consume foods and beverages that elevate insulin levels and blood glucose levels, the plight will continue.

Source: Dr. William Sears, Associate Clinical Professor of Pediatrics, University of California, Irvine, Harvard Medical School, Children's Hospital ((Boston), The Hospital for Sick Children (Toronto); Associate Ward Chief of Newborn Nursery and Associate Professor of Pediatrics.

INSULIN RESPONSE OF SWEET INFUSED FRUITS™

Unlike glucose and other sugars, Sweet Infused Fruits ™ do not stimulate insulin secretion. In clinical trials, “Orally ingested and IV administered SIF were ineffective in eliciting postprandial insulin secretion.”


DIABETIC APPLICATIONS

Sweet Infused Fruits ™ do not elicit a Cephalic Insulin Response in humans, and do not stimulate insulin secretion in humans. SIF are Low Glycemic, Non-Insulin-Cephalic, with a Low Glycemic Load.

Therefore, Sweet Infused Fruits ™ may be used in Type 2 diabetic formulations, including meal replacement drinks and bars, medical feeding formulas, low glycemic ice cream and candies, diabetic candies, and products for diabetic children.

Sweet Infused Fruits ™ have been demonstrated to serve as a useful role in the dietary management of blood sugar levels, since substitution of Sweet Infused Fruits ™ for other simple carbohydrates should lead to reduced post-prandial glucose levels that will aid in overall control.

In persons with type 2 diabetes, the requirement for insulin is greater than that produced by the pancreas.

Sweeteners that produce a lower secretion of insulin and blood glucose are known to be beneficial for glucose metabolism.


RESULTS & BENEFITS

Stimulation of Lipoprotein Lipase (LPL) increases weight gain, obesity, type 2 diabetes, and insulin-resistance.

LPL is the Gatekeeper for fat-Storage in the fat cell.” High glycemic and High-Cephalic ingredients, foods and beverages stimulate LPL.

Abdominal fat Lipoprotein Lipase (LPL) activity contributes to the increased risk for developing obesity-associated diseases.

The leptin content of fat depots as well as plasma insulin concentrations appear in our population as the main determinants of adipose tissue LPL activity, adjusted by gender, depot and BMI.

NO ANIMAL TESTING

Sweet Infused Fruits ™ have never been involved in animal testing. The Sweet Infused Fruits ™ research team are against the abuse of animals in any format, and financially contribute to animal rights groups.

PURITY: Sweet Infused Fruits ™ do not contain any wheat, yeast, soy, sucrose, dairy, salt/ sodium, artificial colors or flavors, gluten or animal derivatives.

STRICT ECO-CONTROLS

Sweet Infused Fruits ™ are solely owned and manufactured by the Sweet Infused Fruits ™ Division of Nutrilab Corporation (www.NutrilabUSA.com). Nutrilab Corporation does not allow anyone else to select the fruit, growers, processing, or any other facet of the development of Sweet Infused Fruits ™. This allows control over the high quality and Bio-Friendly properties.

Sweet Infused Fruits™

Interactions with
Adipose Tissue Deposition,
Leptin & LPL

2007/2009

Orally ingested agents, such as sugars, carbohydrates, and starches, either stimulate LPL or negate its potent fat-storage sequence.

Fat-derived circulating hormones include Leptin, LPL, adipsin, Acrp30/adipoQ (adipocyte complement-related protein of 30 kDa), and Resistin, all primary factors in causing whole-body insulin resistance related to obesity (3).

The accumulation of intracellular fatty acid-derived metabolites is triggered by a mechanism which causes tissue-specific increase in LPL resulting in tissue-specific insulin resistance.

Overexpression of Lipoprotein Lipase, in either liver or skeletal muscle, accumulates lipid (in corresponding tissue) and proceeds to manifest insulin resistance in a tissue-specific manner.

Fat-storage mechanisms in humans involve lipid accumulation due to enhanced fatty acid uptake into the muscle coupled with diminished mitochondrial lipid oxidation. Excess fatty acids are esterified and take one-of-two pathways; they are either stored or metabolized.

The storage versus metabolized routes to various molecules results in the interference with normal cellular signaling, particularly insulin-mediated signal transduction, thus altering cellular and, subsequently, whole-body glucose metabolism.

If not managed by dietary intervention, impaired insulin responsiveness can progress to type 2 diabetes mellitus. For the majority of the human population, this biochemical cascade is avoidable, given that causes of intramyocellular lipid deposition are predominantly diet and lifestyle-mediated.

Chronic overconsumption of foods and beverages that stimulate LPL have been shown to increase the risk of insulin resistance, leading to type 2 diabetes, insulin resistance, obesity, and weight gain.

Since LPL activity can be controlled by adjusting the consumption of LPL-activating foods and drinks, LPL’s profound adipose tissue fat-storing proclivities can be controlled by reducing/eliminating dietary exposure to LPL-stimulating agents.

All sweeteners, carbohydrates, sugars, starches, and other ingredients used in prepared foods and beverages, as well as any raw material, possess intrinsic biochemical characteristics that determine their role in adipose tissue physiology, including its LPL, insulinogenic, blood glucose, glycemic, adipocyte, and fat-storing properties.

Studies of glucose disposal in normal humans shows that skeletal muscle accounts for the majority of insulin-stimulated glucose uptake and that more than 80 percent of this glucose is then stored as glycogen. (Shulman GI et al. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990; 322: 223–228)

The rate of glycogen synthesis in skeletal muscle is 50% lower in diabetic subjects than in normal volunteers. The only other organ capable of storing a significant amount of glycogen is the liver, and glycogen stores are reduced in diabetics.

This glycogen synthesis malfunction in type 2 diabetics is mediated by dietary ingestion of high glycemic foods and drinks, the majority of which contain LPL stimulating ingredients, such as sucrose, glucose, dextrose, maltodextrins, glucose polymers, and other high glycemic raw materials. All high glycemic foods, drinks, and raw materials over-elevate blood glucose levels, and negatively affect insulin and LPL.

In non-diabetics, dietary fat-storage mechanisms are intrinsically the same as in diabetics, yet the reaction in diabetics is profoundly more intense and has more serious implications in blood glucose and insulin imbalance.

Glycogen synthesis malfunction and vital muscle glycogen replenishment cannot be controlled by ingestion of high glycemic carbohydrates, sugars, and starches, which exacerbate insulin resistance, LPL stimulation, and fat-storage into fat cells. Persons with type 2 diabetes are, inevitably, overweight or obese; conditions caused by continual ingestion of high glycemic foods and drinks, as they cause LPL activation.

Artificial sweeteners that have -0- calories, and -0- carbohydrates do not replenish muscle glycogen, thus sports drinks with -0- calories and -0- carbohydrates are contraindicated in sports performance, as they can lead to “Hitting-the-Wall” syndrome, reduced performance, and/or hypoglycemia.

The human body, and particularly the brain, cannot function in a -0- carbohydrate environment. Yet essential carbohydrates, starches, sweeteners, and sugars used in all foods, beverages, and edibles typically elicit high glycemic, fat-storage properties, creating a biochemical cascade of reactive hypoglycemic, sweet-cravings, LPL stimulation, impaired sports performance, reduced cognitive function, and adipose tissue fat-storage.

In 1983, glycemic researchers began developing raw materials that do not possess the metabolic activities of high glycemic sugars, carbohydrates, and starches. In 1997, the process for harvesting the Low Glycemic, Non Cephalic properties from natural fruits had evolved into a feasible and affordable alternative to synthetic and chemical raw materials that stimulate LPL, imbalance Leptin, are high glycemic, and that cause deposition of adipose tissue fat in humans.

The natural fruit extracts are called SWEET INFUSED FRUITS ™. They are derived from this proprietary process, do not stimulate LPL, and have been Certified as “Low Glycemic.”

Following a 20 + year research project, including use of SWEET INFUSED FRUITS ™ in over 250,000 people over a 15 year-period, the Low Glycemic carbohydrates, sugars, and starches derived from SWEET INFUSED FRUITS ™ have been expanded to fulfill market demand for Low Glycemic raw materials.

SWEET INFUSED FRUITS ™ have undergone numerous Human In Vivo Clinical Trials and has proven to be an “Anti-Carbohydrate” (4) in diabetics and non-diabetics.

To ascertain the interaction between SWEET INFUSED FRUITS ™ and Lipoprotein Lipase and Leptin, SWEET INFUSED FRUITS ™ were analyzed to determine thier “anti-carbohydrate” properties and to quantify the precise mechanism by which they stunt adipose tissue fat-storage.

Ramis JM et al, Journal of Nutritional Biochemistry; 2005, demonstrated that “The Leptin content of fat depots as well as plasma insulin concentrations appear in our population as the main determinants of adipose tissue LPL activity, adjusted by gender, depot and BMI” and that “Tissue leptin and plasma insulin are associated with lipoprotein lipase activity in severely obese patients.”

To this end, depot-related and gender-related variances in LPL were examined in non-diabetic obese men and women. Endocrine and biometric factors were rated for their dependence on fat depot and gender. Activity and expression of Lipoprotein Lipase (LPL) were analyzed in adipose tissue fat samples from visceral and subcutaneous fat deposits.

The all-natural SWEET INFUSED FRUITS ™, and their raw material components, are suitable for inclusion in weight management products, as well as all applications in Low Glycemic foods and beverages.

Unlike chemical and synthetic sweeteners, all-natural SWEET INFUSED FRUITS ™ are suitable for children and pregnant women. Additionally, SWEET INFUSED FRUITS ™ do not exacerbate ADD or Dyslexia, and do not stimulate human LPL fat-storing mechanisms.

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