Chapter 1: Diabetes and Obesity: An Overview of Nutritional Effects

Type 2 diabetes (T2D) has evolved into a leading public health concern both for its high prevalence and devastating complications. Current global estimates of 422 million individuals affected by T2D represent a fourfold increase since 1980, with a continued rapid rise.¹  The International Diabetes Federation (IDF) similarly quotes 451 million individuals affected aged 18–99 years in 2017 (8.4%), with a projected prevalence of 693 million or 9.9% by 2045.²  Interestingly, the rise in incidence comes at a time when accumulated evidence clearly demonstrates that T2D is a preventable disease.³  Prior to the 1900s, T2D and obesity were exceedingly rare, affecting two individuals per 100 000 population and 1 in 30 persons, respectively.⁴  The modern-day lifestyle has largely contributed to the overwhelming disease burden, in part due to the increasing availability of processed foods and a sedentary lifestyle facilitated by technology. Obesity, itself, confers a fourfold increase in risk of T2D, and represents the single greatest modifiable risk factor for development of the disease.⁵  In contrast to T2D, Type 1 diabetes (T1D) results from the loss of pancreatic β-cell production of insulin most often through autoimmune mechanisms.⁴  Though patients with T1D also benefit from dietary modification,⁵  strategies for T1D are beyond the scope of this chapter and book, which focus on insulin resistance syndromes. Given the extensive disease morbidity, mortality, and global healthcare expenditure, an intensive lifestyle intervention that includes a nutrient-rich dietary pattern, among other modifications, is vital for prevention and management of these chronic metabolic conditions.^6,7 

The presence of insulin resistance may be demonstrated in patients long before the development of T2D and is believed to serve as the main underlying driver of the disease process.⁸  Obesity predisposes to insulin resistance through a number of complex mechanisms, in part related to increased adipocyte size and quantity and to adipocyte dysfunction.⁹  Adipose tissue, traditionally viewed as simple fat storage, is now more aptly recognized as an active endocrine organ that secretes adipokines, including adiponectin, leptin and resistin, which regulate multiple metabolic pathways involved in glucose homeostasis.^10–12  The excess caloric intake associated with obesity overwhelms adipocyte mechanisms, resulting in dysregulated adipokine secretion, and ultimately a pro-inflammatory state.¹³  Enlarged adipocytes further encourage macrophage recruitment to the tissue, prompting chronic low-grade inflammation.¹⁴  Once established, insulin resistance behaves as a highly disruptive state to regulation of metabolism, exerting widespread effects that include raised glucagon activity during meals that results in inappropriate prandial hepatic glucose release, impaired glucagon-like peptide 1 (GLP-1) release, leptin resistance, reduced ghrelin and adiponectin activity, systemic endoplasmic reticulum stress, systemic inflammation, and pancreatic β-cell dysfunction which culminate clinically as T2D.¹⁵  Similar pathophysiologic mechanisms are observed in other conditions of insulin resistance, including the metabolic syndrome (MetS), hypertriglyceridemia, non-alcoholic hepatosteatosis, and polycystic ovarian syndrome (PCOS).

MetS represents a composite of clinical risk factors that predict insulin resistance, and cumulatively contribute to high risk for atherosclerotic cardiovascular disease (ASCVD).¹⁵  Though published classifications vary slightly, the National Cholesterol Education Program Adult Treatment Panel III defines MetS by the presence of three of the following five parameters: (1) increased abdominal girth (waist circumference >102 cm in men and >88 cm in women); (2) hypertension (systolic blood pressure >130 mmHg and diastolic blood pressure >85 mmHg); (3) elevated circulating triglycerides (>150 mg dL^–1); (4) reduced circulating high-density lipoprotein (HDL) levels (<40 mg dL^–1 in men and <50 mg dL^–1 in women); and (5) elevations in serum glucose concentrations (fasting serum glucose >100 mg dL^–1).¹⁶  Using these criteria, MetS was observed in 33% of adults in the US population in 2012, and demonstrates a rising prevalence worldwide.¹⁷  Due to overlapping pathophysiology, hepatosteatosis, seen in approximately 30% of US adults, and PCOS, observed in 7–10% of reproductive-age women, are also highly prevalent in modern populations.^18,19 

Dietary strategies leading to significant and sustained weight loss can successfully hamper the underlying pathophysiologic mechanisms and mitigate both the development and progression of syndromes of insulin resistance, including T2D and MetS, as well as hepatosteatosis and PCOS by extension (Figure 1.1).

Several landmark trials support the hypothesis that lifestyle interventions leading to weight loss can substantially alter metabolic factors that predispose to T2D and MetS. The first, in 1997, the Da Qing Trial²⁰  in China, involved 577 individuals with impaired glucose tolerance randomly assigned to either conventional lifestyle or one of three treatment groups consisting of dietary intervention, physical activity (PA), or both. All three intervention groups were associated with a significant reduction in the incidence of T2D as compared to control, with an incidence of 67.7%, 43.8%, 41.1%, and 46% with conventional lifestyle, dietary intervention, PA intervention, and both diet and PA interventions, respectively, providing early evidence for lifestyle intervention as a low-cost and effective method of preventing these challenging diseases.

The Finnish Diabetes Prevention Study²¹  (DPS) was another early, randomized trial to demonstrate a causative association between lifestyle modification and T2D prevention in high-risk individuals. The Finnish DPS consisted of 522 overweight adults aged 40–64 with impaired glucose tolerance randomized to either an intensive lifestyle group or a control group receiving standard of care dietary recommendations. With target weight loss of at least 5% body weight, the study showed a 58% risk reduction of developing T2D at 3 years, 43% at 7 years, and 32% reduction at 13-year follow-up compared to the control group. Marked improvement was also noted with respect to glycemic control and cholesterol levels with lifestyle intervention.

In a larger randomized trial of 3234 participants in the United States, the Diabetes Prevention Program²²  (DPP) confirmed the findings of the Finnish DPS by further demonstrating the impact of an intensive lifestyle intervention for the prevention of T2D in high-risk populations. Results from the DPP showed a 58% reduction in the incidence of T2D with an intensive lifestyle program as compared with placebo. This reduction was superior to pharmacologic intervention with twice-daily metformin, which conferred a 31% reduced risk. Those who achieved a target weight loss of at least 7% body weight coupled with 150 minutes of weekly moderate-intensity exercise successfully delayed the progression to T2D by an average of 3 years. The effect was particularly pronounced for those aged 60 or older, with a 71% reduction in T2D onset in this subset of the lifestyle intervention group. Moreover, the ongoing Diabetes Prevention Program Outcomes Study (DPPOS) suggests these preventive effects are sustained with a 27% reduction in the progression to T2D for up to at least 15 years.²³ 

The Look AHEAD trial (Action for Health in Diabetes) similarly studied the impact of lifestyle intervention and weight loss among patients with T2D with regard to risk of diabetes complications, including cardiovascular outcomes and mortality.²⁴  This randomized controlled trial (RCT) involved 5145 overweight or obese participants with known T2D who were assigned to either an intensive lifestyle protocol or standard care. Though the study failed to show benefit with respect to its primary outcome of cardiovascular event reduction, it was notable for a host of important secondary outcomes. Specifically, Look AHEAD showed that a target 5-kg weight reduction improved glycemic control and was associated with a 30% reduced risk of kidney dysfunction, a particularly detrimental microvascular complication of T2D.²⁵  Additionally, scores of erectile function, depression, and quality of life were overall improved, with 11% lower rate of hospitalization, and 6% reduced medication requirements among the intensive lifestyle group.^26–28  Moreover, a post-hoc analysis showed study participants who successfully lost weight had an approximate 15% reduction in cardiovascular outcomes for every 7% of weight lost.²⁹  Accordingly, the Look AHEAD trial provides large-scale evidence of the effect of an intensive lifestyle program on clinically relevant and patient-important outcomes in patients with T2D.

Observational studies have further clarified the role of dietary modification in prevention of the microvascular complications of T2D, including blindness, kidney failure, and lower-limb amputation. The Nurses’ Health Study demonstrated that a diet high in fruit, vegetables, nuts, and lean meat (Dietary Approaches to Stop Hypertension (DASH)-style pattern) was associated with a 40% reduced risk of microalbuminuria compared with a Western diet.³⁰  Similarly, a cohort study of 978 participants in Japan demonstrated a 52% reduction in diabetic retinopathy associated with high fruit intake following 8 years, independent of glycemic control.³¹  A high-fiber diet also was associated with reduced incidence of both retinopathy and microalbuminuria in a cohort study of 1272 subjects in India.³²  These studies highlight the substantial impact of a nutrient-rich diet on both the onset of T2D as well as its debilitating complications (Table 1.1).

The dietary strategies utilized among these studies primarily focused on a low-fat, high-fiber, calorie-restricted diet in addition to regular moderate-intensity exercise and frequent contact with individual lifestyle coaches. This is in line with the prevailing recommendation of a low-fat diet in past years. However, optimal macronutrient dietary content has been challenged more recently. Though several dietary strategies have been proposed, the dietary pattern individuals choose to adopt is less vital to their outcome than adherence level. Most importantly, dietary strategies should be practical and feasible to encourage long-term adherence. As diet remains a highly personalized choice, influenced by culture, religion, and socioeconomic status, among other factors, the unifying concept is that long-term adherence is ultimately what predicts successful weight loss. In a randomized trial comparing four popular diets in 160 overweight or obese individuals, each diet achieved comparable levels of weight loss and cardiovascular risk factor reduction after 1 year, but amount of weight loss correlated more strongly with adherence level rather than type of diet.³³  All diets performed poorly with respect to self-reported adherence, highlighting the importance of choosing a dietary pattern most in keeping with one’s lifestyle and preferences. The large RCTs to date included a level of supervision not feasible in the general population. Adherence often suffers under real-world circumstances, and is a notable barrier to achieving the level of benefit seen in clinical trials.

Carbohydrates take on a variety of forms and pervade the modern diet as starch, glycogen, other polysaccharides, or simple sugars (monosaccharides and disaccharides). Fructose has become increasingly prevalent in the modern diet owing to the industrial availability and use of sucrose and high-fructose corn syrup (HFCS). HFCS was introduced in the 1960s as an inexpensive, liquid sweetener, which was liberally applied to commercial products for added flavor.⁴  Sugar-containing beverages in particular gained much attention for their high HFCS content, wide availability, and weighty contribution to both childhood and adult obesity. Sucrose, the main industrial alternative to HFCS, has almost the same fructose content, differing by a mere 5%.

Fructose-containing sweetened beverages have been shown to increase postprandial triglycerides, and reduce both leptin levels and insulin secretion.³⁴  Perhaps unsurprisingly, intake of soft drinks and fruit drinks has been independently associated with the development of the MetS and T2D.³⁵  Moreover, those with a genetic predisposition to obesity are more prone to develop this disease with high intake of sugar-sweetened beverages.³⁶  In countries with higher availability of HFCS, an approximate 20% increase risk of T2D is observed in comparison to countries with lower availability.³⁷ 

Mechanistically, fructose fails to trigger both the insulin and leptin responses typical in carbohydrate metabolism.³⁸  In the short term, intake of fructose seems to have temporizing blood glucose effects without a sharp serum glucose rise, and has therefore been utilized as a common agent for diabetic supplements. However, the benefits are short-lived and the associations with chronically high fructose intake and worsening insulin resistance and T2D become readily apparent over time. Another detriment to fructose is the hunger response and increased caloric intake elicited, due in part to (1) promoting leptin resistance, thereby decreasing satiety and losing regulation of food intake, and (2) stimulating dopamine receptors within the nucleus accumbens, triggering a pleasure response. Over time repeated sugar intake results in a downregulation of dopamine receptors, inducing a withdrawal response when the sugar stimulus subsides.⁴  On the cellular level, fructose metabolism is poorly regulated as it enters the glycolysis pathway downstream of an important regulatory and rate-limiting step, resulting in disordered energy metabolism and fatty acid production. Finally, fructose increases de novo lipogenesis, reduces insulin sensitivity, promotes dyslipidemia, and drives central adiposity as compared with glucose.³⁹  By these mechanisms, it is not surprising that a high dietary fructose intake has been strongly implicated in several metabolic conditions, including T2D, MetS, PCOS, obesity, vascular disease, and hepatosteatosis.

In light of current evidence, the American Heart Association recommendation is to limit daily simple sugar intake to no more than 37.5 g, or 9 teaspoons, of sugar for men and 25 g, or 6 teaspoons, for women. Similarly, in 2015, the World Health Organization proposed that sugar comprise no more than 10% of total energy and ideally less than 5%.

Fructose naturally exists in fruits, honey, and agave-derived syrups though in low quantities (4–8 g), and in many cases the presence of fructose is counterbalanced by fiber, which helps to slow absorption, as well as mixed with other antioxidants and vitamins that may offset potential harms.

Dietary fiber constitutes another class of carbohydrate that may be further subdivided into polysaccharides and modified polysaccharides, or insoluble and soluble forms. Insoluble fibers are largely indigestible and therefore structurally useful for bulking chyme and stool as well as slowing gastric emptying. Soluble fibers are inherently more viscous and help to line the intestinal tract and delay absorption of dietary carbohydrates and lipids.⁴⁰  Further, soluble fiber plays an integral role in altering the flora of the gut microbiome and subsequently in the production of short-chain fatty acids, which both serve as an energy substrate and play a pivotal role in gut immunity.⁴¹ 

The gut microbiome is a highly individualized environment vulnerable to type, quality, and source of food.⁴⁰  Though the microbiome naturally exists as a symbiosis of bacteria, fungi, and host organisms, it remains susceptible to alterations inflicted by lifestyle. Different dietary sources supply different substrates for microorganism growth, for example, allowing certain bacteria to flourish and others to perish depending on dietary content. Studies comparing the microbiome of children in urban and rural areas identify a relative increase in Firmicutes bacteria and reduction in Bacteroidetes based upon the dietary patterns endemic to those areas. Specifically, children in urban areas were found to have a microbiome dominated by organisms apt to break down animal fat, protein, and sugars, whereas children in more rural areas harbored organisms better equipped to break down dietary fiber and carbohydrates from vegetable sources.⁴²  Importantly, a diet rich in fat and simple sugars, characteristic of the Western diet, results in a depletion of protective organisms and a disruption of symbiotic mechanisms, which can manifest clinically as obesity, among other diseases.⁴⁰  Diets deficient in fiber, the so-called “fiber gap,” result in an additional depletion of favorable microbiota which metabolize fiber to short-chain fatty acids.^41,43 

Glycemic index is another useful marker by which to classify carbohydrates and signifies the rapidity with which they are absorbed and utilized. High-glycemic foods are typically high in monosaccharides or easily digestible polysaccharides, low in dietary fiber, and have greater potential to evoke harmful periods of serum glucose peaks. High-glycemic foods should be avoided or minimized as able in individuals with T2D, and preferably paired with fat, protein, or other food items which may delay absorption and temper glucose elevations. Perhaps a more comprehensive measure of glucose content is offered by the glycemic load, which takes into account both the glycemic index and portion size, or the amount of simple carbohydrates consumed. Glycemic load may act as a more telling indicator of glucose content of any given food intake under more real-world circumstances.

A low-fat diet has long been touted primarily for its potential to reduce low-density lipoprotein (LDL) cholesterol that comprises atherosclerotic plaques and predisposes to cardiovascular disease. Both observational studies and RCTs have elicited mixed results with respect to dietary fat and insulin resistance, obesity, and T2D. More recently, a higher-fat diet has fallen into favor when taking into account the type of fat consumed. Specifically, monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have garnered much attention for their capacity to reduce LDL cholesterol and improve insulin sensitivity, and their benefits are very much apparent in the Mediterranean diet (MedDiet), where healthy MUFAs and PUFAs, e.g., in the form of olive oil and nuts, are abundant.

In the midst of widespread obesity, several dietary patterns have been proposed to target excess weight and improve metabolic parameters, including insulin resistance. Though the philosophies of each of the proposed diets are similar at their core, nuances exist that generally differentiate each on the basis of macronutrient ratio. General principles focus on high intake of fruit, vegetables, fiber, and high-quality fats, and liberal intake of antioxidants and vitamins, while minimizing carbohydrates, and in particular fructose.

The MedDiet has proven one of the most successful dietary strategies to date, both for its weight loss potential and position as the single diet shown to improve cardiovascular outcomes and mortality among overweight and obese individuals, including those at high cardiovascular risk. The MedDiet, first described in the 1960s based on traditional dietary practices common in the Mediterranean region, favors a diet composed primarily of fruits, vegetables, nuts, and whole grain cereals, with an emphasis on fish and moderate red wine intake, and restricted in dairy, red meat, and processed foods. The MedDiet is mainly distinguished by its ample use of olive oil, nuts, red wine, fatty fish, as well as tomatoes, garlic, onions, and spices simmered in olive oil, with these nutrient-rich ingredients likely behaving in synergy to enhance the overall metabolic environment.⁴⁴  The PREDIMED randomized, multicenter trial conducted in Spain was a landmark study designed to confirm observational studies that showed promise for the primary prevention of cardiovascular disease with the MedDiet.⁴⁵  In the PREDIMED trial, 7447 participants deemed high-risk but without proven cardiovascular disease were randomly assigned to one of three interventions: (1) MedDiet enriched with extra-virgin olive oil; (2) MedDiet enriched with mixed nuts; or (3) a control, low-fat diet. Following 5 years, the two groups assigned a MedDiet supplemented with extra-virgin olive oil or with nuts performed similarly, with a 30% reduction in cardiovascular events in comparison to the control low-fat diet. As coronary disease remains the leading cause of mortality in the United States,⁴⁶  results of the PREDIMED trial are highly relevant. With regard to T2D, a post-hoc analysis of the PREDIMED trial demonstrates a 30% reduction in the incidence of T2D, and of the 3614 subjects with known T2D, the MedDiet supplemented with extra-virgin olive oil reduced the incidence of diabetic retinopathy by 40%, though no risk reduction was observed in the incidence of diabetic nephropathy.

Another large, randomized trial compared three common dietary patterns: low-fat diet, low-carbohydrate diet, and the MedDiet among 322 obese subjects. After 2 years, subjects assigned to the low-carbohydrate diet achieved the greatest mean weight loss (4.7 kg), followed closely by the MedDiet (4.4 kg), with the least weight loss observed with a low-fat diet (2.2 kg). Of the 36 patients with T2D included in the trial, the MedDiet proved the most effective for reducing fasting blood glucose levels.⁴⁷  Further, a systematic review of eight meta-analyses and five RCTs comparing the MedDiet to a low-fat or control diet concluded a 19–23% reduced risk of incident T2D with the MedDiet, and a reduced glycosylated hemoglobin of 0.3–0.47% in those with established T2D.⁴⁸  In this study and others, the MedDiet has the additional potential benefit of ameliorating all components of MetS.⁴⁹ 

The social ritual of wine with meals is another nutrient-rich custom of the Mediterranean population. The nutritional benefits of wine have long been studied, largely in conjunction with alcohol in general, with cardioprotective effects credited to an increase in HDL cholesterol. More specific to wine is a high polyphenol content, sevenfold greater in red wine than white, which has been associated with improved glycemic control, reduced retinopathy, blood pressure-lowering effects, and reduced markers of inflammation.⁴⁴  A study of 224 subjects with T2D on the MedDiet examined the effects of both red and white wine on metabolic parameters. Participants were randomized to receive 150 mL of red wine, white wine, or water daily for a duration of 2 years. Interestingly, the study noted both wine intervention groups to reduce fasting insulin, but with an average reduction of 18 mg dL^–1 in subjects receiving white wine, and a 2 mg dL^–1 average increase in HDL cholesterol with red wine intervention.⁵⁰ 

Resveratrol in particular, a polyphenol present in peanuts, grapes, and red wine, has been extensively studied for its protective role in cancer, cardiovascular disorders, oxidative stress, neurodegenerative disease, glucose homeostasis, and obesity, among others.⁵¹  In animal models, resveratrol consistently improves insulin resistance by activating sirtuin-1 and adenosine monophosphate-activated kinase, and reducing systemic inflammation.⁵²  Sirtuins, a class of histone deacetylases, have been implicated in the mechanism of caloric restriction and extended lifespan. Compounds that activate the sirtuin pathway and its metabolic effects, such as resveratrol, are highly favorable.^53,54  Human trials examining oral supplementation with resveratrol in T2D, though limited in number and short in duration, are similarly promising.⁵⁵  A study of 62 subjects with T2D randomized to resveratrol 250 mg day^–1 or standard of care demonstrated improved hemoglobin A1c (HbA_1c), systolic blood pressure, and total cholesterol with resveratrol over 3 months, without significant change in HDL or LDL cholesterol.⁵⁶  Moreover, a randomized placebo controlled trial of 24 participants with known MetS assigned to either trans-resveratrol 500 mg three times daily before meals or placebo for 90 days displayed significant benefit in body weight, body mass index (BMI), fat mass, waist circumference as well as area under the curve (AUC) of insulin, and total insulin secretion with resveratrol intervention, though no differences were found with respect to blood pressure, fasting glucose, postprandial glucose levels, AUC of glucose, or first phase of insulin secretion.⁵³ 

The “French paradox” has been described as a phenomenon of reduced ischemic cardiac disease despite a high intake of saturated fat observed within French culture. The drivers for this are still poorly understood but may include the cardioprotective effects of red wine, among other aspects of French cuisine. Current views suggest red wine may additionally offset a high saturated fat intake by inhibiting platelet aggregation, rather than promoting atherosclerosis, and in this regard may be a particularly beneficial component of the MedDiet.⁵⁷ 

Olive oil, rich in MUFAs, is an important staple of the MedDiet that contributes to the prevention and management of T2D. A high-MUFA diet, when compared to a high-carbohydrate diet, reduces fasting plasma glucose and favorably impacts triglycerides, weight, systolic blood pressure, and HDL cholesterol.⁵⁸  In further support, a meta-analysis of 29 RCTs and four cohort studies including 15 784 patients found the highest intake of olive oil to be associated with a 16% reduced risk of developing T2D as compared with those with the lowest intake.⁵⁹  The published clinical trials and studies investigating individual components provide strong evidence for the benefits of the MedDiet. The implementation of the MedDiet is among the best options for the treatment and prevention of metabolic disease, including T2D.

The New Nordic Diet (NND) models the cuisine typical of the local Scandinavian region and, in many ways, closely resembles the core of the MedDiet, including large quantities of vegetables, fruits, whole grains, and fish. The difference lies in more distinctly Nordic ingredients, including rapeseed oil in place of olive oil, local vegetables and fruit, and a focus on fresh berries, herbs, and wild mushrooms. While large trial data assessing outcomes of NND is limited, a study performed in Denmark that included obese subjects randomized to either the NND or Danish diet, comparable to the Western diet, determined a 6-kg versus 2-kg weight loss in the NND and control group, respectively. Moreover, markers of insulin resistance, including fasting serum glucose and insulin levels, as well as serum triglyceride levels, were significantly reduced with NND intervention.⁶⁰  Results from the SYSDIET randomized trial assessing the NND in 200 obese subjects with MetS showed the NND diet to improve both lipid profiles and markers of low-grade inflammation at 18–24 weeks as compared with placebo, suggesting a potential role for this strategy in both T2D and MetS.⁶¹ 

The Ornish Diet (OD) favors a predominantly plant-based strategy with significant limitation of animal fat and its derivatives, and a subsequent increase in carbohydrates. Specifically, the diet endorses 75% complex carbohydrates, 15% fat, and 10% protein, supplemented with ample fruit and vegetables. The benefit of the OD has largely been observed with respect to LDL cholesterol and atherosclerotic disease. Though data is limited, one randomized control study found a similarly structured whole-food, vegetarian diet, high in complex carbohydrates, to be associated with regression of atherosclerotic plaques and less than half the number of coronary events over 5 years, among patients with known coronary atherosclerotic disease.⁶² 

Given the high carbohydrate content, the benefit of the OD in T2D is less clear.⁶³  A brief prospective cohort study assessing the effect of a plant-based, whole-food, low-fat diet on cardiac biomarkers in 131 subjects with established or high-risk coronary artery disease noted improvements in all studied cardiac parameters, including a fasting glucose reduction of 15 mg dL^–1 and HbA_1c reduction of 0.4% in diabetic subjects after 3 months.⁶⁴  The Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart) similarly studied three diets with varied macronutrient ratios on insulin sensitivity in overweight and obese subjects, including a high-carbohydrate diet, comparable to the DASH diet, a diet partially replacing carbohydrates with protein, and a diet partially replacing carbohydrates with unsaturated fats, similar to the MedDiet. The study concluded that the diet with a higher ratio of unsaturated fats increased markers of insulin sensitivity more effectively than either the high-carbohydrate diet or protein diet.⁶³ 

The very-low-carbohydrate ketogenic diet has reemerged in recent years for its potential to induce profound weight loss and widespread metabolic effects. Prior to the advent of insulin in the 1920s, severe caloric and carbohydrate restriction, the so-called “starvation diet,” was the main therapeutic option by which those with diabetes could potentially delay complications of the disease.^65,66  Traditionally developed for refractory epilepsy, the ketogenic diet has since expanded to treat a multitude of disorders, including neurodegenerative disease, traumatic brain injury, cancer, acne, diabetes, and obesity.⁶⁷ 

The ketogenic diet proposes a stringently low carbohydrate intake, < 20 g day^–1 or <10% of daily caloric intake, with calories replaced primarily by fat in an effort to induce a state of nutritional ketosis. Limited in available carbohydrates, fat becomes the predominant fuel source, and is metabolized by the liver into fatty acids and ketone bodies, in the form of acetoacetate and 3-beta-hydroxybutyrate. These compounds enter circulation and are then utilized for systemic energy needs.^67,68 

Current large-scale evidence on the effect of the ketogenic diet on T2D remains limited. One randomized trial of 84 obese subjects with T2D assigned participants to either a low-carbohydrate ketogenic diet or a low-glycemic index diet for a duration of 24 weeks. While both diets led to significant weight loss and improved metabolic markers, the low-carbohydrate ketogenic diet was far superior in reducing HbA_1c (–1.5% vs. –0.5%) and weight (–11.1 vs. –6.9 kg), with notable gains in HDL cholesterol (+5.6 vs. 0 mg dL^–1). Moreover, the low-carbohydrate ketogenic diet reduced or eliminated medication requirements in almost all participants (95.2%) versus 62% observed with a low-glycemic index diet.⁶⁹ 

A larger study of 363 participants with excess weight enabled participants to select either a low-carbohydrate ketogenic diet or low-calorie diet for a duration of 24 weeks. Here, too, both diets improved the tested parameters, including body weight, BMI, waist circumference, blood glucose level, HbA_1c, and lipid profile, but effects on blood glucose level and HbA_1c were substantially greater with the low-carbohydrate ketogenic diet, with an additional 22.5 mg dL^–1 reduction in blood glucose (99 vs. 121.5 mg dL^–1), and 1.5% reduction in HbA_1c (6.25% vs. 7.75%).⁷⁰ 

In a comparison of the efficacy of a low-carbohydrate diet versus low-fat diet in the treatment of T2D and obesity, an important study of 132 severely obese subjects (BMI >43 kg m^–2) randomized to low-carbohydrate or low-fat diet for 6 months found subjects on the low-carbohydrate diet to have a significantly greater weight loss (–5.3 vs. –1.9 kg) and improvement in both triglycerides (–38 vs. –7 mg dL^–1) and insulin sensitivity than their fat-restricted counterparts. In addition, subjects with T2D who underwent a low-carbohydrate diet reduced fasting blood glucose by 26% as compared with 5% on a low-fat diet.⁷¹ 

Given the potential cardiac consequences of a high-fat diet, a randomized trial of 53 obese women investigated a very-low-carbohydrate diet consisting of no more than 20 g carbohydrates per day, or a calorie-restricted, low-fat diet for 6 months with the primary outcome of weight loss and cardiovascular risk factors. The very-low-carbohydrate diet achieved greater weight loss without detriment to blood pressure, lipids, serum glucose, and insulin levels despite high fat intake.⁷² 

A meta-analysis of 13 RCTs including 1415 patients comparing a very-low-carbohydrate ketone-generating diet with a low-fat diet over at least 12 months demonstrates greater weight loss, greater reduction in triglycerides, lower diastolic blood pressure, greater HDL, though slightly higher LDL with a weighted mean difference of 4.6 mg dL^–1 among individuals assigned to a ketogenic diet in comparison to those on a low-fat diet.⁷³  The observed increase in LDL cholesterol was attributed to an increase in saturated fat intake, though this is notably contradicted by additional studies which associate a reduction in LDL cholesterol with the ketogenic diet.^74,75  Interestingly, one study showed an increase in LDL cholesterol observed with a high-fat, low-carbohydrate diet to primarily affect the less atherogenic larger-sized LDL cholesterol, rather than the more harmful small, dense LDL cholesterol.⁷⁶ 

Thus, the ketogenic diet has proven generally safe, when used judiciously. Caution should be used in patients with renal dysfunction due to a potentially larger protein intake, or those on insulin for whom hypoglycemia remains a high risk. For appropriate candidates, the general recommendation is that the diet be undertaken alongside a healthcare professional with frequent metabolic monitoring (Figure 1.2).

Micronutrients, encompassing electrolytes, vitamins, trace elements, and plant alkaloid compounds, are an essential yet often overlooked component of a comprehensive and nourishing diet. Micronutrients are responsible for a wide array of metabolic processes that promote overall health, including glucose metabolism, free radical scavenging, and clearance of advanced glycosylated end products (AGEs).⁷⁷  Several micronutrients have garnered interest as a natural adjunct to traditional T2D treatment strategies. The impact of micronutrients may perhaps be most clearly seen in the context of obesity and T2D, where deficiencies are common.

Chromium (Cr), present in the diet within yeast, egg yolks, meat, whole grains, and cereals, is a known cofactor of insulin signaling and has been investigated for its potential role in glucose and lipid metabolism.⁷⁸  Chromium, bound to the oligopeptide chromodulin, is present intracellularly, where it prolongs insulin action by activating insulin receptor kinases and inhibiting insulin receptor phosphatases. It has further been postulated that chromium plays a role in the upregulation of insulin receptors, and facilitates uptake of glucose at target tissues.^79,80  The overall effect is enhanced insulin sensitivity, and reduced insulin requirements in individuals with T2D.⁸¹ 

Chromium was first recognized for its role in carbohydrate metabolism in animal models in the 1950s and similar effects were subsequently demonstrated in humans in the late 1970s. Observations of patients receiving prolonged parenteral nutrition that did not include chromium developed severe insulin resistance and hyperglycemia, which quickly resolved with chromium supplementation. Initial high insulin requirements declined to zero.⁸²  Chromium is now a standard component of current parenteral nutrition formulations.⁸³ 

Clinically, chromium levels are distinctively lower in patients with T2D as compared with normal subjects, by as much as 20–40% lower in the serum and 40–50% lower in scalp hair.⁷⁷  Lower concentrations of chromium in toenails have additionally been associated with a higher risk of developing T2D.⁸⁴  Chromium supplementation in the form of chromium picolinate has shown marginal benefit in markers of glycemia and lipids. A randomized trial of 180 subjects with T2D assigned to chromium 100 µg or 500 µg twice daily versus placebo showed chromium supplementation to afford minor improvements in glucose parameters following 4 months.⁸⁵ 

More recently, a randomized trial of 71 patients with poorly controlled T2D (HbA_1c >7%) receiving 600 µg of chromium supplementation demonstrated a similarly small but significant improvement in glycemic measures, including fasting and postprandial glucose reductions of 17 mg dL^–1 and 25 mg dL^–1, respectively, and HbA_1c reduction of 0.9% as compared with placebo without demonstrable effects on serum lipid concentrations.⁸⁶  A pooled analysis of 28 RCTs indicated a significant reduction in fasting blood glucose, HbA_1c, triglycerides, and an increase in HDL cholesterol with chromium supplementation.⁸⁷  At the same time, other published trials fail to demonstrate benefit of chromium supplementation in patients with T2D,⁷⁸  and current knowledge does not yet substantiate its routine use in the management of T2D.

Selenium, obtained through the diet as nuts, meats, eggs, and cereal, is another trace element implicated in T2D, though data here, too, remains mixed. Early rodent studies demonstrated reduced insulin resistance when treated with selenate, an inorganic form of selenium.⁸⁸  In humans, one RCT of selenium supplementation in obesity revealed a 10% reduction in fasting insulin levels,⁸⁹  and in subjects with gestational diabetes, selenium reduced overall fasting plasma glucose by 10 mg dL^–1 and fasting plasma insulin by 1.98 IU mL^–1.⁹⁰ 

Studies have recognized selenoproteins, particularly glutathione peroxidase (GPx-1), as the key mechanism by which selenium exerts its effects. GPx-1 has a somewhat paradoxical effect; this enzyme scavenges free radicals and prevents oxidative damage, and it catalyzes biochemical redox reactions which result in antioxidant production.⁷⁷  On the other hand, rodent models have identified overexpression of GPx-1 to cause hyperglycemia, and GPx-1 knockout mice accordingly have better glycemic control than their wild-type counterparts. Given these dual aspects, selenium may most judiciously be consumed in quantities that ensure satisfactory levels while avoiding oversupplementation.⁹¹ 

Importantly, a number of studies have demonstrated either no benefit or, in fact, an increase in incidence of T2D with selenium supplementation.⁹²  In the late 1990s, selenium gained attention in the Nutritional Prevention of Cancer trial in which supplementation with selenium 200 μg daily was assessed for the primary outcome of non-melanoma skin cancer. In secondary analyses, selenium demonstrated a notable reduction in the incidence of colorectal and prostate cancers, though at the expense of an unexpected increase in incident T2D. Specifically, the study reports 58 new cases of T2D in the selenium intervention group as compared with 39 cases in the placebo group (hazard ratio 1.55 (95% confidence interval, 1.03–2.33)).⁹³  A systematic review of 13 observational studies and three RCTs indicates conflicting results, with observational studies concluding a positive correlation between serum selenium levels and T2D and RCTs failing to show an association.⁹¹  Current data is insufficient to make recommendations regarding selenium intake or supplementation for benefits in T2D.

Though classically associated with calcium homeostasis and bone metabolism, vitamin D has more recently been implicated in a number of other conditions, including cardiovascular disease, cancer, autoimmune disease, T2D, and obesity.⁹⁴  Vitamin D insufficiency and overt deficiency, defined as serum levels <20 mg dL^–1 and <30 mg dL^–1 respectively, are highly prevalent in obesity, affecting up to 80–90% of obese individuals.^95,96  The presence of vitamin D receptors and 1-alpha hydroxylase activity, the enzyme responsible for vitamin D activation, in human pancreatic beta cells provides compelling evidence for a potential mechanism of vitamin D in glucose homeostasis.⁷ 

Current data is overall insufficient to either advocate or invalidate the role of vitamin D in obesity, MetS, and T2D. Observational studies showing initial promise have since been called into question by randomized clinical trials and meta-analyses. Still, some studies do offer the potential for benefit, if only small. A recent meta-analysis of 24 RCTs assessing the effect of vitamin D supplementation on markers of glycemic control demonstrates statistically significant reductions in fasting plasma glucose (–4.9 mg dL^–1), HbA1c (–0.30%), and homeostasis model assessment of insulin resistance (HOMA-IR) (–0.66) with vitamin D supplementation.^97,98  Moreover, supplementation with vitamin D 500 IU daily demonstrated a notable 13% reduction in the risk of T2D when compared with a slightly lower dose of 200 IU daily. Subjects with higher serum 25OH-vitamin D levels, above 25 ng mL^–1, were shown to have a 43% risk reduction for developing T2D compared to those with lowest levels below 14 ng mL^–1.⁹⁴ 

More commonly, RCTs that study vitamin D supplementation in T2D fail to demonstrate a consistent and significant benefit.⁹⁹  An RCT of 62 vitamin D-deficient participants with T2D treated with high-dose supplementation versus placebo found no difference in insulin sensitivity or glucose homeostasis markers as measured by euglycemic clamp method following 6 months.⁹⁷  Similarly disappointing, studies assessing vitamin D supplementation in obese individuals have proved largely unsuccessful in demonstrating weight loss, despite the well-established association between obesity and vitamin D deficiency.^99–101  High-dose vitamin D₂ supplementation in subjects with MetS additionally failed to show improvement in HOMA-IR after 8 weeks, suggesting vitamin D may not influence this composite of metabolic risk factors.¹⁰²  Future studies may more clearly delineate the role of vitamin D by using optimal and standardized dosing, longer durations, larger sample sizes, consistency in baseline vitamin D status, and more direct measurement rather than surrogate markers of glucose homeostasis.¹⁰³ 

Cinnamon is a common household spice that has been postulated to facilitate glycemic control in T2D.¹⁰⁴  The first potential role for cinnamon in glucose metabolism originated in 2003 in a clinical trial of 60 men and women with T2D conducted in Pakistan.¹⁰⁴  In this population, cinnamon, supplied in three separate dosages, was equally effective in reducing mean fasting plasma glucose (18–29%), triglycerides (23–30%), LDL cholesterol (7–27%), and total cholesterol (12–26%) levels over a 40-day span. However, a study in the United States that randomized 57 subjects with T2D to 1 g cinnamon daily or placebo for 3 months failed to show significant differences between the two groups with respect to BMI, HbA_1c, cholesterol, triglycerides, or insulin levels in the background of a Western diet.¹⁰⁵  A meta-analysis of 10 RCTs published in 2013 noted variable doses of cinnamon to be associated with reduced fasting plasma glucose, total cholesterol, LDL cholesterol, and triglyceride levels with a statistically significant increase in HDL cholesterol. However, no difference was found with respect to glycosylated hemoglobin, and studies were widely disparate in terms of dosing and follow-up times.¹⁰⁶  The American Diabetes Association currently adopts the position that there is insufficient evidence to support the use of cinnamon or other natural supplements in the treatment of T2D, though a potential benefit should be considered along with a minimal potential risk.

Plant alkaloids are a large group of naturally occurring substances with unique biochemical properties. Many exhibit antioxidant effects, and some may have benefits for the treatment and prevention of T2D, though further study is needed (Figure 1.3).

T2D and obesity are well known for their capacity to induce extensive morbidity, costly medical care, and ultimately, shortened lifespan. Of further urgency, these conditions have reached epidemic proportions globally. As with other chronic conditions, the most effective strategy for combating these diseases is often prevention. An intensive lifestyle intervention affords an opportunity to both prevent T2D and mitigate its potential complications. Moreover, nutrition therapy leading to weight loss targets the underlying process of insulin resistance, and therefore additionally improves parameters of MetS, PCOS, and hepatosteatosis, among other conditions.

For these reasons, dietary strategies are increasingly deserving of scientific attention. Future studies, particularly long-term studies, can provide a better understanding of the role of nutrition, specific dietary patterns, and micronutrients in these common disorders of insulin resistance. In particular, future studies may address more personalized approaches to diet, in which specific dietary patterns are undertaken to target specific metabolic derangements, and investigate efforts to improve adherence. Dietary adherence remains a major barrier to achieving sustained weight loss, and thus a reasonable, palatable diet should be a central focus of management.