Journal of the American College of Nutrition, Vol. 26, No. 2, 83-94 (2007)
Published by the American College of Nutrition
Dietary Management of Type 2 Diabetes: A Personal Odyssey
Frank Q. Nuttall, MD, PhD, FACN, MACN and
Mary C. Gannon, PhD, FACN
Section of Endocrinology, Metabolism & Nutrition, and the Metabolic Research Laboratory, Department of Veterans Affairs Medical Center (F.Q.N., M.C.G.)
Department of Medicine (F.Q.N., M.C.G.)
Department of Food Science & Nutrition (M.C.G.), University of Minnesota, Minneapolis, Minnesota
Address reprint requests to: Frank Q. Nuttall, M.D., Ph.D., Chief, Endocrinology, Metabolism & Nutrition, Professor of Medicine, VA Medical Center/University of Minnesota, One Veterans Drive, Minneapolis, MN 55417, E-mail: nutta001{at}umn.edu
Key words: diabetes, diet, dietary protein, dietary carbohydrate, glycemic index, starvation, glycogen, glycogen synthase
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Introduction
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It often is stated that "diet is the cornerstone" of diabetes treatment. However, which diet(s) should be recommended for people with diabetes has been, and remains controversial. During the lecture presented as recipients of the American College of Nutrition Award for 2006, at the American College of Nutrition 47th Annual Meeting, our objective was to provide a synopsis of our research related to the metabolic effects of macronutrients at a basic science and clinical level. We also invited the audience to view our "professional journey" along the path that led to our current view of the dietary management of type 2 diabetes.
Our work has focused on macronutrients, that is carbohydrates, proteins and fats. The majority of our data relates to metabolic effects of dietary proteins and carbohydrates. Our work on dietary fats is incomplete at this time.
Four issues will be highlighted: 1). The effect of sugars and starches on blood glucose in type 2 diabetes. 2). The effect of reducing the total carbohydrate in the diet on blood glucose in type 2 diabetes. 3). The effect of dietary protein on insulin and glucose concentrations. 4). The integrated effect of these in the design of a diet for people with type 2 diabetes.
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Diabetes Classification
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Diabetes can be classified several different ways, but most commonly it is divided into 2 large groups, type 1 diabetes and type 2 diabetes. Type 1 is most common in children. In this type of diabetes the ß cells have been destroyed by an autoimmune process. Thus insulin production has ceased. For all practical purposes, the only treatment for this condition is insulin replacement.
Type 2 diabetes is most common in adults. In type 2 diabetes, the ß cell mass is reduced [1,2], resulting in an impaired ability to make insulin. It also appears that the remaining ß cells are relatively blind to the blood glucose concentration, in that they do not respond appropriately to an increase in the concentration of glucose, but do so to non-glucose insulin secretagogues [3]. Traditionally, treatment has consisted of recommending weight loss, since many subjects are obese. This usually fails. Oral agents are then begun. If oral agents are ineffective, or lose their effectiveness, insulin treatment is instituted.
The overall objective of our clinical research has been to develop a diet that does not require weight loss or medications, but still controls blood glucose in people with type 2 diabetes. The goal is to enable the person with type 2 diabetes to control their blood glucose by adjustment in the content rather than the amount of food energy in their diet.
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A Personal Odyssey by the Senior Author
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My investigative scientific career began with studies I did on the regulation of glycogen synthase as a graduate student in the laboratory of Joseph Larner, M.D., Ph.D., Department of Biochemistry, University of Minnesota. In Dr. Larner's laboratory, the structure and regulation of glycogen synthase in heart, skeletal muscle and liver were being studied. I was assigned to study the regulation of glycogen synthase in the heart.
Dr. Larner received his training in the laboratory of the Nobel Laureates, Carl and Gerty Cori. They were the first to demonstrate that an enzyme (glycogen phosphorylase) could be present in two forms, and one form could be converted into another by a separate enzyme [4,5].
Subsequently, Drs. Fischer and Krebs demonstrated that the interconversion of the two forms of phosphorylase was due to a phosphorylation-dephosphorylation mechanism catalyzed by enzymes. They also received a Nobel Prize. Dr. Krebs also received his training in the Cori Laboratory. Dr. Larner demonstrated that skeletal muscle glycogen synthase was regulated by a phosphorylation-dephosphorylation mechanism as well. It was the second enzyme shown to be regulated in this fashion. It now is known to be the most common covalent means of regulating enzymes. Indeed, hundreds of enzymes are regulated by the attachment and removal of phosphoryl groups.
Glycogen synthase is the rate-limiting enzyme in glycogen synthesis. It transfers the glucose moiety of UDP-glucose to the terminal branches of glycogen, causing the glycogen molecule to enlarge. A mature glycogen molecule contains thousands of glucose molecules all attached to each other in a highly branched spherical structure.
Glycogen synthase in heart and muscle is present in two inter-convertible forms, an inactive form, and a catalytically active form. Glycogen synthase is converted into the active form by a phosphatase enzyme which removes several phosphates from the inactive form of the enzyme. Our laboratory showed for the first time that insulin stimulated the phosphatase activity [6]. Later others reported that insulin inhibited glycogen synthase kinase-3 (GSK3) [7], an enzyme which converts the active form back to the inactive form. Thus, glycogen synthesis in heart and muscle is regulated by insulin.
However, my own interest was in the regulation of glycogen synthase in the liver. Thus, when I left the Larner laboratory, I began studying the structure and regulation of liver glycogen synthase. By this time, Dr. Gannon had joined the laboratory and brought to the laboratory her background in nutritional biochemistry, as well as her expertise in human nutrition. The reason that we were interested in the liver is because we considered it to be the metabolic fuel control center of the body. Or at least it functions as the metabolic fuel transformation center.
Nevertheless, Dr. George Cahill referred to it as the "dumb liver" because it only does what it is told to do by other regulatory systems. These systems interrogate the internal and external environment and send signals to the liver. In this scenario, the liver faithfully responds by varying its metabolism, storage and release of metabolic fuels. However, the liver probably is not so dumb after all. More recent data indicate the presence of a sophisticated intrinsic regulation of glucose production [8–10] and probably gluconeogenesis as well [10].
Whereas insulin regulates glycogen synthase activity in skeletal muscle and heart [6,11–19], we demonstrated that in the liver, synthase activity is largely regulated by the intracellular concentration of glucose [20–30], fructose [31–34] and/or galactose [25], with fructose being most potent. These monosaccharides activate glycogen synthase by stimulating synthase phosphatase activity [35] (Fig. 1).
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Fig. 1. Regulation of glycogen synthase in liver. Glycogen synthase is converted from the inactive form, synthase D, to active synthase R forms, by a phosphatase, which is stimulated by glucose, fructose, and galactose in liver. The reverse reaction is catalyzed by kinases, which are stimulated by glucagon, epinephrine and vasopressin in liver.
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Even though glucose, galactose and fructose are metabolized through different pathways (Fig. 2), they all serve as substrates for glycogen synthesis and all regulate the activity of liver glycogen synthase. That is, not only are these monosaccharides substrates for glycogen synthesis, but they also regulate their own disposition in the liver, a very elegant system.
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Fig. 2. Pathways of glucose, galactose and fructose metabolism in liver. Glucose, galactose and fructose all serve as substrates for glycogen synthesis. In addition, as indicated in Fig. 1, all regulate the activity of glycogen synthase.
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Because of the regulatory activity of these monosaccharides, we developed an interest in the regulation of the glucose, fructose and galactose concentrations in the circulation, and thus in the liver cell.
Subsequently, we provided data in the rat which demonstrated that the removal of fructose derived from the oral administration of fructose is so efficient in the liver that the concentration of fructose in the peripheral circulation is always very small [32,33,36]. On the other hand, very little glucose is removed by the liver during the first pass [37], even though about 20% of the ingested glucose eventually becomes incorporated into liver glycogen. Dr. Niewoehner, from our laboratory, also demonstrated that galactose is an excellent substrate for glycogen synthesis and that it activates glycogen synthase [38].
So in summary, glucose, galactose, and fructose derived from ingested carbohydrate-containing foods, enter the portal vein and are carried to the liver. The liver rapidly clears fructose from the circulation and a large proportion is stored as glycogen. When galactose is ingested as lactose, it also is rapidly removed by the liver, but less so when ingested independently [3]. Glucose on the other hand goes through the liver into the peripheral circulation where it stimulates insulin secretion (Fig. 3). The latter is important because a rise in glucose and insulin concentration is a signal to the body in general, to transition from a fasted to a fed state. Again, a very elegant regulatory system.
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Fig. 3. Absorption of glucose, fructose, and galactose. Glucose (glu), fructose (fru) and galactose (gal) derived from ingested carbohydrate containing foods enter the portal vein and are carried to the liver. The liver rapidly clears fru and gal from the circulation and a large proportion is stored as glycogen. Glucose on the other hand goes through the liver into the peripheral circulation where it stimulates insulin secretion.
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Data from our and Dr. Niewoehner's laboratory also indicated that orally administered fructose [32] and galactose [38] either have only a modest effect on peripheral blood glucose or no effect at all in rats. Interestingly, both glucose [39] and galactose [38], but not fructose [32], were shown to be taken up by the liver against a concentration gradient. Based on this information, we considered it likely that it is the glucose component that raises blood glucose, when sucrose or lactose is ingested by humans.
Having worked with rats and mice intensively for several years, Dr. Gannon and I developed a severe allergy to rats and mice. Therefore, we discontinued our studies using these animals. In addition, one of my children's teachers asked what kind of a doctor I was, and the response was "Oh, he's not a real doctor, he's a RAT doctor!" This was a further inducement to change the direction of my research. Furthermore, humans, metabolically speaking, are not just 70 kg rats. We then decided to study glucose, fructose and galactose metabolism in humans.
As an endocrinologist, I also was interested in the management of diabetes and in particular, the management of type 2 diabetes.
We also went on to highly purify the human liver synthase enzyme, determine its phosphate content (13–17/subunit) and the phosphoryl changes that occur when the enzyme is activated and inactivated [40]. Subsequently we cloned and sequenced the liver synthase gene [41], and demonstrated its location on the short arm of chromosome 12 [42]. We also clearly demonstrated that the gene as well as the structure of the liver enzyme is different from that of the heart and skeletal muscle enzyme, and the gene is located on a different chromosome [43].
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Effect of Sugars and Starches on Blood Glucose in People with Type 2 Diabetes
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As a consequence of our rat studies, we also became interested in determining whether the rise in peripheral glucose concentration in humans was largely due to the glucose component of all foods in people with type 2 diabetes. As mentioned previously, the metabolizable carbohydrates important in human nutrition are the monosaccharides glucose and fructose, the disaccharides sucrose and lactose, and the polysaccharides, the starches. In rats, fructose and galactose are avidly removed by the liver and we consider it likely to be true in humans. So if only diet-derived glucose is responsible for raising the blood glucose, then the glucose response to sucrose and lactose, since they are 50% glucose, should be half of that to a starch containing food, which is largely pure glucose.
We began this work by doing single food, single meal studies. The glucose area response to 50 g of glucose, 50 g of carbohydrate as corn flakes (starch) and 50 g of carbohydrate as sucrose or lactose in shown in Fig. 4. The glucose area response to 50 g glucose was set at 100%. Under these circumstances the ingestion of 50 g of carbohydrate in the form of corn flakes was 101% [44], the glucose area response to sucrose was 42%, and the area response to lactose was 33% [45]. Thus, the glucose area response to sucrose and lactose were actually less than the 50% area response, i.e. the expected response if only glucose was important in raising the blood glucose concentration. The theoretical glucose area response to corn flakes actually should have been 111% of that of glucose. The lower than expected glucose area response to corn flakes and to sucrose could be attributed to a greater than expected insulin area response. The reason the lactose area response was less is unclear. In any regard, the glucose response to sucrose and lactose was considerably less than even the observed response for corn flakes.
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Fig. 4. Effect of 50 g starch or 50 g sugar ingestion on glucose and insulin area response in people with type 2 diabetes. The glucose (left) and insulin (right) area response to ingestion of 50 g of glucose, 50 g of carbohydrate as corn flakes and 50 g of carbohydrate as sucrose or lactose. Adapted from [44,45].
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In other studies we also determined that the fructose concentration was only 1 mg/dl before and only 6 mg/dl after ingestion of 50 g fructose [36]. When 25 g of fructose was ingested, the expected maximal concentration would only be 2 mg/dl. When 50 g of lactose was ingested, which contains 25 g of galactose, the galactose concentration in the peripheral blood remained undetectable [46]. Thus, in humans with type 2 diabetes, our research group determined that it is the glucose content of foods that is largely responsible for raising blood glucose after single meals, just as in non-diabetic rats. The liver is very efficient in removing both fructose and galactose from the portal blood coming from the intestines. Incidentally, the simultaneous ingestion of glucose, independently, or in the form of lactose is necessary for the efficient hepatic removal of galactose (reviewed in [3]).
As indicated above, the earliest studies were done using single foods. We next were interested in determining whether substitution of starches with sugars in mixed meals would result in a decrease in circulating glucose concentration when the total carbohydrate content of the meals was similar.
The common sources of readily digestible starches are cereals, potatoes, rice, pasta, etc. The major sources of sucrose are fruits, fruit juices, and some vegetables. Again, the carbohydrate content of sucrose-containing foods is basically 50% glucose, 50% fructose. The only source of lactose in the diet is from milk products. As indicated previously, lactose is composed of 50% glucose, 50% galactose. Thus, if we substitute sources of starches in the diet with foods containing sucrose and lactose, again theoretically, the glucose area response after mixed meals should be only 50%, i.e. when sugars are substituted for starches, the glucose area responses after mixed meals should be decreased by 50%.
Therefore, we designed a study in which the carbohydrate content of two test meals was basically the same, the protein content was basically the same, and the fat content was similar [47]. The control meals were referred to as "American meals" and contained the typical ratio of carbohydrate:protein:fat (40:20:40) consumed in the United States when the study was done. The low starch meals contained essentially the same composition (43:22:34), but no starch. Six males with untreated type 2 diabetes were studied. They received 3 identical meals of either the "American meal" or "low starch meal" at 8 am, noon, and 5 pm with a snack at 9 pm on two separate occasions, in random order. The meals were isocaloric and we determined the glucose and insulin concentrations over 24 hours.
The glucose excursions when subjects ingested the American diet and the low starch diet are shown in Fig. 5. As mentioned previously, the carbohydrate content in the two different meals was essentially the same. Using the fasting glucose concentration as a baseline, the glucose area response was integrated over 24 hours. The mean glucose area response during the 24-hour period when the subjects ingested the "low starch" meals, (i.e. a lower glucose content diet) was only 5% of that when they ingested the "American meals". The mean 24-hour insulin area response was 54% of that following the "American meals".
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Fig. 5. Effect of meal carbohydrate composition on glucose response in 6 males with type 2 diabetes. The mean glucose excursions when subjects ingested the "American diet" are shown in the broken line and the low starch diet in the solid line. B, L, D, and S indicate the time that breakfast, lunch, dinner, and a snack were ingested. The net area responses are shown in the inset. Using the fasting glucose concentration as baseline, the area response to the low starch meals was only 5% of the response to the "American meals". Adapted from [47].
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From these studies we concluded that substituting starch-containing foods with sugar-containing foods in mixed meals could markedly reduce post meal glucose excursions even though the carbohydrate content was similar. In fact, just as was noted when single foods were ingested, the reduction in post meal glucose concentration again was greater than expected and considerably less than the theoretical if the fructose and galactose were rapidly removed by the liver but there was little removal of glucose. The reason for the smaller than expected glucose rise after meals remains to be determined.
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The Glucose Concentration is Unstable when Determining the Glucose Area Response to Single Meals
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In our early studies in which we determined the 5-hour glucose area response to single foods in people with type 2 diabetes, we used just the fasting, premeal glucose concentration as a baseline. In later studies we always used a water control. That is, when the subjects were given a single food, we gave the same subjects only water on a separate occasion over the same 5-hour period of the study, and compared the results. This was because we had observed a rather dramatic decrease in the blood glucose concentration when the subjects are given only water after an overnight fast. Thus, in order to accurately determine the effect of a specific food, the intrinsic decrease in plasma glucose when the subjects are given only water should be used as the basis for determining the glucose area response. This will result in a larger area response in all cases than if only the premeal glucose concentration is used in quantifying the glucose response to a food. It will not change the ordering of food effects, but it will affect the quantitative differences. The latter can be highly significant in understanding the metabolic response. Insulin values are not profoundly different [48].
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The Effect of Short-Term Starvation on Blood Glucose
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The fact that even very short-term fasting markedly affected the glucose concentration stimulated us to determine the effect on plasma glucose of extending the length of the fast. We also were intrigued since starvation is the most extreme case of carbohydrate restriction. At that time we were not aware of the excellent study by Faiman and Moorehouse in 1967, who reported a similar decrease in blood glucose when untreated diabetic subjects were starved for a short period of time [49].
We therefore designed a study in which 7 males with untreated type 2 diabetes were fasted for a 24-hour period following an 11 hour overnight fast [50]. There was a dramatic decrease in the blood glucose concentration going from approximately 158 mg/dl at 8 am down to 104 mg/dl at 7 pm. The glucose concentration then increased moderately to 130 mg/dl at 7 am the following morning. In some subjects we continued the fast for another 24 hours, and the blood glucose continued to decrease (Fig. 6). We only half facetiously have stated that we can cure diabetes within 12 hours.
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Fig. 6. Effect of an extended fast on blood glucose concentration in subjects with untreated type 2 diabetes. After an overnight fast of 11 hours, 7 subjects were fasted for 24 hours (closed circles; adapted from [50]). Four subjects continued the fast for another 24 hour fast, i.e. 48 hour fast (open circles).
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The Effect of Reducing the Total Carbohydrate in the Diet on Blood Glucose in People with Type 2 Diabetes
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Since short-term starvation resulted in a dramatic decrease in blood glucose without significant weight loss, we asked the question, "Could merely a reduction in carbohydrate mimic the effect of a reduced fuel-energy diet or short-term starvation on blood glucose in people with type 2 diabetes mellitus?"
We designed studies in which subjects with type 2 diabetes received a low carbohydrate-but food energy adequate diet, i.e. a carbohydrate-semi-starvation state. We also increased the protein content of the diet. This was done for two reasons. First, it allowed us to reduce the carbohydrate content without raising the fat content, which many nutritionists would find objectionable, and second, we and others had demonstrated that dietary protein stimulated insulin secretion without raising the glucose concentration. Our introduction to, and data regarding the potency of dietary protein in stimulating insulin secretion in people with type 2 diabetes is reviewed below.
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Dietary Protein and the Effect on Plasma Insulin and Glucose
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In 1980, diets for people with diabetes were constructed using a food exchange system developed in 1950. In the 1971 edition of Joslin's Diabetes Mellitus [51] the food exchange system was described as follows: "Each food in a list (or group) contains about the same amount of carbohydrate, protein or fat as any other food in that list." Foods were grouped into 6 large categories. There was a milk exchange group, a vegetable exchange group, a fruit exchange group, a bread exchange group, a meat exchange group and a fat exchange group. The exchange system was widely used by dietitians to design diets for people with diabetes. Although a food exchange system was developed in 1950, we were surprised to find that in the subsequent 30 years, the appropriateness of this approach had never been studied. We decided to address this issue by designing 4 single mixed meals using the food exchange list approach. The plasma glucose response to each was determined over a 4-hour period. These meals theoretically should all have had the same amount of carbohydrate, protein and fat [52]. For example, the carbohydrate content was expected to be 67, 67, 65, 65 grams in the 4 meals.
Indeed, the 4-hour glucose area responses were similar for 3 of the 4 meals. However, more importantly, we had determined the glucose and insulin response to 50 g of glucose in these subjects before they ingested the defined mixed meals to document that they were indeed diabetic. We were surprised to find that even though a mixed meal contained more carbohydrate (65 g), and more potentially available glucose (61 g vs 50 g), ingestion of the mixed meal resulted in a glucose area response that was only 70% of that when 50 g glucose was ingested. Of more interest, the serum insulin was dramatically increased relative to that following the ingestion of 50 g glucose. Indeed, is was 215%.
Fats generally do not raise serum insulin. The amount of glucose in the diet could not explain the exaggerated rise in insulin. Fructose and galactose, we had previously shown, only weakly stimulated insulin secretion. Therefore, this suggested that is was the protein content in the meals that was stimulating the very large rise in insulin concentration.
We therefore decided to determine whether dietary protein could explain the very large increase in serum insulin concentration noted above. We did a study in which 7 subjects with type 2 diabetes [53], and 8 normal subjects [54] ingested 50 g of protein in the form of very lean beef. In the normal subjects, there was no change in blood glucose concentration over the 4 hours of the study. In the subjects with type 2 diabetes, the glucose concentration decreased over the 5 hours of that study (Fig. 7).
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Fig. 7. Glucose (left panel) and insulin (right panel) response to ingestion of 50 g protein in the form of very lean beef in 7 subjects with type 2 diabetes (broken line) and 8 subjects without type 2 diabetes (solid line). Adapted from [53,54].
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We observed a modest increase in the insulin concentration in the normal subjects, as reported previously by others [55–57]. However, in subjects with type 2 diabetes, there was a relatively enormous increase in insulin concentration (Fig. 7). Thus, dietary protein could essentially explain the greater insulin response when mixed meals were ingested compared to the ingestion of 50 g glucose per se.
We subsequently determined that meat protein and glucose were equipotent in stimulating insulin secretion in people with type 2 diabetes [53]. In normal subjects, protein was only 28% as potent as glucose in stimulating insulin secretion [54].
Since beef protein, when ingested alone, strongly stimulated insulin secretion, we considered it important to determine whether the simultaneous ingestion of protein with glucose would further increase insulin secretion and decrease the circulating glucose response, and if so, whether all proteins were equal in this regard.
We designed a study in which males with untreated type 2 diabetes were given 50 g of glucose with or without 25 g of protein. Seven protein sources were used: beef, turkey, gelatin, egg white, cottage cheese, fish and soy [58]. We gave 25 g of protein with 50 g of glucose because this ratio more closely resembled the ratio of protein to carbohydrate in the normal American diet. The plasma glucose and serum insulin concentrations were determined over a 5-hour period and the areas under the curves were calculated.
The glucose area response to ingestion of 50 g glucose alone was set at 1 (or 100%). When each protein was ingested with glucose, the plasma glucose area response was less than when only glucose was ingested, with the exception of egg white. The most dramatic effect was seen with cottage cheese and gelatin. We subsequently reported that egg white most likely is only slowly digestible [59,60]. This potentially could explain the small effect of egg white.
When protein was ingested with the glucose, the insulin area response was greatly increased. The smallest response was obtained with egg white, which was 190% or 1.9 fold that of glucose. The greatest increase was with cottage cheese, which was 360% or 3.6 fold that of the response when glucose was ingested alone. Since we had previously reported that the insulin area response to glucose and beef were equal on a weight basis [53], and since we gave only 25 g of protein and 50 g of glucose, the anticipated increase in insulin concentration following the ingestion of beef with glucose would be 50% greater. With every protein source studied, the insulin response was greater than the theoretical expected response, strongly suggesting that there is a synergistic insulin response when protein is ingested with glucose by people with untreated type 2 diabetes.
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The Effect of Dietary Protein on the 24 Hour Integrated Glucose Concentrations
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Based on the above observation, we then designed a 5-week study in which the protein content of the diet was increased from 15 to 30% of food energy at the expense of carbohydrate, and provided it to subjects with untreated type 2 diabetes. The postprandial glucose concentrations were attenuated and the insulin response was increased as might have been expected [61]. However, the basal glucose concentration was unchanged over the 5 weeks of the study.
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Summary of Effects of Dietary Carbohydrates, Proteins and Fats
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In summary, in people with untreated type 2 diabetes, dietary protein strongly stimulates insulin secretion and decreases the plasma glucose response to ingested glucose. Only dietary carbohydrates increase the blood glucose and this is due largely to the glucose content of foods. Dietary glucose strongly stimulates insulin secretion. Fructose and galactose are relatively weak, but still significant insulin secretagogues. Fats most likely have little or no effect on either glucose or insulin. The effect of dietary fats is not reviewed here and needs to be studied in a more definitive fashion. We are doing such studies in our laboratory at the present time. Finally, reducing the glucose content of the diet and increasing the protein and fat content should reduce the postprandial plasma glucose concentration in people with diabetes. Reducing the total carbohydrate content could mimic a semi-starvation state and thus reduce the fasting glucose as well.
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Integrated Effect of Responses to Macronutrient Ingestion (LoBAG Diets)
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The above principles have been incorporated into a comprehensive approach to the dietary management of untreated type 2 diabetes. Specifically we have designed a diet in which the total carbohydrate is decreased, the composition of the carbohydrate has been changed, i.e. the starch has been decreased, and the protein content has been increased. We refer to these diets as low biologically available glucose diets, or LoBAG diets.
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LoBAG20 Diet
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In our initial study, we increased the protein content of the diet from 15% in the control diet to 30% in the LoBAG diet, and decreased the carbohydrate content from 55% in the control diet to 20% in the LoBAG diet. We refer to this diet composition as a LoBAG20 diet. The subscript refers to the % of food energy as carbohydrate in the diet. In order to accommodate this macronutrient mix, we increased the fat content to 50% (11% saturated fat), from 30% in the control diet. We studied 8 men with untreated type 2 diabetes, in a randomized crossover design [62]. Subjects were on each diet for 5 weeks with a washout period in between. The diets were isocaloric, the patients were weight stable, and as before, we provided all of the food [61].
The body weights were stable during both diets for the duration of the study. Twenty-four hour serum beta-hydroxybutyrate data at the end 5 weeks on the control diet and at the end of the LoBAG20 diet were very similar. These subjects were not ketotic. (This is NOT the Atkins diet.)
The major end-point of the study, or primary outcome measure was to determine if there was a significant decrease in total glycohemoglobin (%tGHb). The rationale for a using 5 weeks as a time frame is that the t1/2 for glycated hemoglobin (or HbA1c) to reach a new steady state after a change in 24 hour integrated glucose concentration is reported to be 
35 days or 5 weeks [63]. Therefore, the ultimate change in glycohemoglobin is likely to be twice that observed in a 5-week study.
Ingestion of the LoBAG20 diet resulted in a markedly attenuated glucose rise after breakfast, lunch, dinner and a snack (Fig. 8). Consequently, the total 24-hour integrated area data, using the initial plasma glucose concentration as baseline, was decreased by 77%. In addition, and perhaps more importantly, the fasting glucose concentration decreased from 168 mg/dl at the beginning of the LoBAG20 diet to 120 mg/dl after 5 weeks on the diet. That is, the overnight fasting glucose concentration mimicked that produced when men with type 2 diabetes were fasting 11 hours overnight, and then for an additional 10 hours [50].
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Fig. 8. Effect of diet on plasma glucose concentration. Mean 24-hour glucose response at the beginning (control diet, open circles) and after 5 weeks of ingesting a LoBAG20 diet (closed circles) in 8 men with untreated type 2 diabetes. Inset: Net and total 24 hour integrated glucose area responses. Net area is calculated using the fasting value as baseline. Total area is calculated using zero as baseline. Adapted from [62].
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The fasting insulin concentrations were similar at the beginning and end of the 5 weeks on the LoBAG20 diet. The post meal concentrations were greatly attenuated, and the total 24-hour integrated area responses were decreased by 25% (Fig. 9).
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Fig. 9. Effect of diet on serum insulin concentration. Mean 24-hour insulin response at the beginning (control diet, open circles) and after 5 weeks of ingesting a LoBAG20 diet (closed circles) in 8 men with untreated type 2 diabetes. Inset: Net and total 24 hour integrated insulin area responses. Adapted from [62].
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At the end of the 5 weeks, the mean %total glycohemoglobin had decreased from 9.8 to 7.6, i.e. 2.2%, and was continuing to decrease at the end of the study. The %tGHb was 9.8% at the beginning of the control diet, and 9.8% after 5 weeks on the diet.
Since the decrease in %tGHb seen at 5 weeks is only 50% of the expected final decrease, the expected final effect on %tGHb is shown in Table 1. The anticipated final GHb would be 5.4%, i.e., well within the normal range for our laboratory (reference range = 4.0–6.3).
To put this decrease in glycohemoglobin into perspective, we consulted the Physicians Desk Reference for 2003. Rosiglitazone or metformin are drugs commonly used to treat people with type 2 diabetes. Rosiglitazone, when given at a maximum dose for 16 weeks resulted in a mean decrease of 0.7% in HbA1c. Metformin, at a maximum dose, after 29-weeks, resulted in a mean decrease of 1.4%. With the LoBAG20 diet, over the 5 weeks of our study, the decrease was 2.2%. The final anticipated result would be a decrease of 4.4%, i.e. the decrease was greater than that obtained using the above two medications.
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LoBAG30 Diet
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More recently we have designed a diet in which the carbohydrate has been increased from 20% to 30% of total food energy. This allowed the fat content to be decreased from 50% to 40%.
When the carbohydrate was increased from 20% (LoBAG20) to 30% of total food energy (LoBAG30), the decrease in %tGHb at 5 weeks was 1.7%, or an ultimate anticipated decrease of 3.4% (Fig. 10) (unpublished data).
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Fig. 10. Effect of LoBAG diets on % total glycohemoglobin. Composite data on the effect of a control diet (top line, open circles) or diets with decreasing percentages of carbohydrate (LoBAG40, LoBAG30, LoBAG20) in people with untreated type 2 diabetes. Adapted from [61,62, 65].
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Caveats
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While these results are quite compelling, we still consider our studies to be "proof of concept" studies. Our patient population is predominantly male, the number of subjects in each study is small, the studies are not of a long duration, and our food choices are limited by purchasing and budget constraints. Nevertheless, the decrease in glycohemoglobin is highly significant and reproducible. The diet is acceptable to our patients over at least 10 weeks (unpublished data). However, long-term compliance could be a major issue.
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Postscript
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Since our LoBAG diets are unlike (an anathema) to those recommended by several professional organizations and government agencies, we would like to end with a quote from E.F. DuBois in 1928 regarding the diabetic diet. "It would almost seem as if we made an advance each time we adopted a diet diametrically opposed to the one that preceded it" [64].
We also would like to quote from two of the critiques we received from an NIH study section in 2002, when our research proposal was summarily turned down for funding. From one reviewer:" ... the PI estimates that a difference in the HbA1c changes of 1.5% can be detected with 18 subjects. A change of this magnitude is rarely seen in the most rigorous intervention; it is unlikely that two [sic] diets which maintain body weight will produce changes in HbA1c which differ by even 0.5%, which would require several hundred subjects to reach statistical significance." On resubmission, a reviewer stated, "In the sample size determination, the PI estimates that a difference in the HbA1c changes of 1.5% can be detected with 18 subjects. In studies comparing the effect of anti-diabetic medications with placebo, presumably a larger effect difference than that produced by two [sic] diets, the change in HbA1c are [sic] in the range of 0.4–1.2%. It is difficult to conceive of the diet as producing larger improvements than metformin or rosiglitazone, for example, especially if the subjects are maintaining their body weight." These comments were made in spite of our providing preliminary data indicating that the proposed diet could profoundly lower blood glucose and the %tGHb. So much for open mindedness!
It is a great honor for us to receive the 2006 Annual American College of Nutrition Award. It is most deeply appreciated.
We also are greatly indebted to the funding agencies that have supported our research over the years. These are: The Department of Veterans Affairs; The National Institutes of Health; The National Dairy Council; The National Dairy Promotion & Research Board; The Minnesota Beef Council; The Nebraska & Colorado Beef Councils; Minnesota Medical Foundation; The American Diabetes Association, Minnesota Affiliate; and The national American Diabetes Association
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ACKNOWLEDGMENTS
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Dr. Nuttall would like to like to acknowledge 2 people who had a major influence on his professional career. George Cahill, a friend and colleague stimulated his interest in fuel metabolism. Indeed, Dr. Nuttall considers Dr. Cahill to be his role model.
Dr. Nuttall also would like to recognize Joseph Larner, who was his advisor and mentor during the pursuit of a Ph.D. in biochemistry. Dr. Larner stimulated Dr. Nuttall's interest in metabolic control systems, and particularly in enzyme regulation.
Finally, the authors want to acknowledge all the people involved in their studies over the past several decades. These studies are very labor intensive, and could not have been done without the collaboration of colleagues, trainees and students, as well as our superb technical staff.
Colleagues, trainees and students: Daniel P. Gilboe, Ph.D.; Kristine L. Larson, D.V.M.; Randall T. Curnow, M.D.; Jose Barbosa, M.D.; William J. Bergstrom, M.D.; Mohammed Ahmed, M.D.; Victor A. Corbett, M.D.; Agnes W.H. Tan, Ph.D.; James A. Thomas, Ph.D.; Mark P. Wheeler, M.D.; Carole J. Kyllo, Ph.D.; Laurence N. Mulmed, M.D.; Norman D. Olson, M.D.; Dennis D. Doorneweerd, M.D.; Anthony S. Tan, M.D.; John J. Regan, M.D.; James W. Theen, M.D.; Barbara B. Chow, Ph.D.; Michael F. Slag, M.D.; John E. Morley, M.D.; Arshag D. Mooradian, M.D.; Catherine B. Niewoehner, M.D.; Byron J. Hoogwerf, M.D.; Gregory A. Nuttall, M.D.; Bryan Q. Nuttall, B.S., M.B.A; Jennifer A. Nuttall Martinson, M.D.; Philip A. Krezowski, M.D.; Charles J. Billington, M.D.; Brian J. Neil, M.D.; Sydney A. Westphal, M.D.; Elizabeth R. Seaquist, M.D.; Ernest Y.C. Lee, Ph.D.; Ge Bai, Ph.D.; David Bernlohr, Ph.D.; Linda Brady, Ph.D.; Paul Brady, Ph.D.; Lynn A. Burmeister, M.D.; James T. Lane, M.D.; Kathryn L. Pyzdrowski, M.D.; Mehmood A. Khan, M.D.; Nacide Ercan-Fang, M.D.; Kevin J. Sheridan, M.D.; Sean Fang, M.D.; Vinendra Gupta, M.D.; Charles R. Sandhofer, M.D.; Charles T. Grant, M.D.; Virginia L. Kubic, M.D.; Marju Orho, Ph.D.; Leif C. Groop, M.D.; David J. Holtschlag, M.S.; Munir Abid, M.D.; Neng Qian Chen, Ph.D.; Sergio Scapin Ph.D.; J. Bruce Redmond, M.D.; Gregory A. Damberg, M.D.; Asad Saeed, M.D.; Michael A. Kuskowski, Ph.D.; Sidney A. Jones, M.D.; Virginia L. Rath, Ph.D.; Judith L. Treadway, Ph.D.; Youssef Hassan, M.D.; Kelly Jordan Schweim, Pharm. D.; Bradford Johnson, M.D.; Nicole Nader, M.D.; Zoobia W. Chaudhry, M.D.; Angela Ngo, M.D.; Angela Schiteanu, M.D.
Technical Staff: Robert DeMarais, R.D.; Shirley Parker, R.D.; Jean L. Wald, R.D., M.S.; Carol Labresh, B.A.; Leslee Kollins; Diane Miller, B.A.; Heidi Hoover, R.D., M.S.; Rita F. Lamusga, M.T.; Nancy Anderson, M.T.; Marilyn Menninga, M.T.; Helen Ofstad, B.S.; Marie E. Matlack, M.T.; Joanna Aretz, B.S.; Faye Fang, B.S.; Beverly Hesby, M.T.; Nancy Hale, M.T.; Cara Beasley, B.S.; Ping Pei, B.S.; Kari J. Hoyt, B.S.; Beverly Hesby, M.T.; Beverly Lundell, M.T.; Miriam R. Taylor, B.S.; Mary J. Adams, M.T.; Jan Thurgood, B.A.; Linda Hartich, B.S., M.T.; Laura Gillispie, R.D.; Rachel Gramith, B.S.
This is a review of our own work. However, we would like to acknowledge the work of many superb investigators whose data we depended upon for formulating and carrying out these studies and which we were not able to include in the review.
Lastly, we would like to thank each other. We are a team and what we have accomplished could not have been done independently.
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FOOTNOTES
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This paper is an excerpt of the lecture presented at the 47th Annual Meeting of the American College of Nutrition, in Reno, Nevada, October 7, 2006, by Drs. Nuttall and Gannon, recipients of the American College of Nutrition Award for 2006.
The authors do not have a personal financial interest in the work or with a commercial sponsor.
Received January 8, 2007.
Accepted March 2, 2007.
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Introduction
Diabetes Classification
