ABSTRACT

Severe obesity represents a major risk factor for the development of type 2 diabetes mellitus (T2DM). Due to the strong association of obesity and diabetes, the term “diabesity” was coined, suggesting a causal pathophysiological link between both phenomena. The majority of individuals with T2DM are obese, highlighting the pivotal role of increased adiposity as a risk factor for diabetes. However, only a relatively small fraction of obese individuals will develop T2DM. On a population level, the link between obesity and its secondary complications is well described. However, the molecular mechanisms underlying these complications are still poorly understood. Three main hypotheses have been developed in recent years to bridge the gap between epidemiology and pathobiochemistry: (1) The “inflammation hypothesis” asserts that obesity represents a state of chronic inflammation where inflammatory molecules produced by infiltrating macrophages in adipose tissue exert pathological changes in insulin-sensitive tissues and β-cells. (2) The “lipid overflow hypothesis” predicts that obesity may result in increased ectopic lipid stores due to the limited capacity of adipose tissue to properly store fat in obese subjects. Potentially harmful lipid components and metabolites may exert cytotoxic effects on peripheral cells. (3) The “adipokine hypothesis” refers to the principal feature of white adipose cells to function as an endocrine organ, and to secrete a variety of hormones with auto- and paracrine function. Expanding fat stores can cause dysfunctional secretion of such endocrine factors, thereby resulting in metabolic impairment of insulin target tissues and eventually failure of insulin producing β-cells. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Severe obesity represents a major risk factor for the development of type 2 diabetes mellitus (T2DM), a disease characterized by insulin resistance, insulin hyposecretion and hyperglycaemia.^1-3 According to statistics, already 415 million people worldwide were affected by diabetes in 2015 (estimated) and this number is expected to rise to 642 million by 2040.⁴ Due to the strong association of obesity and diabetes, the term “diabesity” was coined, suggesting a causal pathophysiological link between both phenomena.^5,6

SIZE MATTERS (NOT ONLY)!

The majority (~80%) of individuals with T2DM are obese, highlighting the pivotal role of increased adiposity as a risk factor for diabetes. However, only a relatively small fraction of obese individuals develops T2DM.⁷ In fact, most obese, insulin-resistant individuals do not develop hyperglycemia, indicating that their pancreatic β-cells still produce and secrete sufficient amounts of insulin in order to compensate for the reduced efficiency of insulin action in the periphery.^1,8,9 Thus, in addition to an increased adipose mass, additional factors are likely to determine the risk for β-cell dysfunction and the susceptibility for β-cell destruction and diabetes. Nevertheless, despite recent advances in the understanding of body weight regulation and insulin action, the risk factors that determine which obese, non-diabetic individuals will eventually develop diabetes still remain unknown.

ROLE OF FAT DISTRIBUTION

Obesity results from a period of a positive energy balance during which adipocytes store excess triglycerides, resulting in cell hypertrophy and hyperplasia. However, fat depots do not expand uniformly as they accumulate lipids, and the adverse effects of excess fat storage have been frequently attributed to intra-abdominal (i.e. visceral) fat tissue. Using a variety of measures (oral glucose tolerance test, intravenous glucose tolerance test, euglycemic hyperinsulinemic clamps), selective excess of visceral adipose tissue (visceral adiposity) has been linked to insulin resistance in humans.^10-19 Interestingly, no relationship between visceral fat and impaired glucose metabolism has been observed in studies with non-obese individuals.^20,21 On the other hand, other studies found that abdominal subcutaneous fat correlates with insulin sensitivity as well as visceral fat in euglycemic clamps, thus challenging a unique role for the visceral fat depot in modulating insulin sensitivity.^22,23 However, in another study, Klein and coworkers reported that large-volume abdominal liposuction of subcutaneous fat did not improve insulin sensitivity of liver, skeletal muscle, and adipose tissue (as assessed by euglycemic-hyperinsulinemic clamps), at least not within 12 weeks post surgery.²⁴ In accordance to these results, removal of visceral fat has been found to improve insulin sensitivity in humans,^25,26 supportive of a causal role of intra-abdominal fat for the insulin resistance in obese individuals. However, the relationship between the amount of visceral fat and insulin sensitivity has been controversially discussed throughout recent years and a number of clinical studies show that surgical removal of this fat depot (e.g. via omentectomy) did not lead to improved whole-body glycemia or even BMI of the patients.^27-30 Interestingly, a number of adipose-tissue related sub-phenotypes have been identified, one of these the so-called “TOFI” (“thin on the outside, fat on the inside”) subjects. These patients present a normal BMI (< 25 kg/m²) but increased abdominal obesity and therefore exhibit an increased risk to develop insulin resistance and T2DM.^31,32 In contrast to TOFI, the so-called “fat-fit” subjects show no gross impairments of glucose metabolism despite their elevated body adiposity (BMI ≥ 30 kg/m²).^32,33

Visceral fat is defined as adipose tissue located inside the peritoneal cavity—within the parietal peritoneum and transversalis fascia, excluding the spine and paraspinal muscles. As such, appropriate techniques for precise measurements of visceral fat, however, have been controversial. In humans, the amount of abdominal visceral fat is determined by a number of different techniques, including anthropomorphic measurements (waist-hip-ratio, waist circumference, abdominal sagittal diameter), computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound. Comparative measurements using CT and MRI have revealed a fairly high correlation between both methods.^34-36 In the recent years, Dual-energy X-ray absorptiometry (DXA) has emerged as reliable technique to measure body composition with high-precision, low X-ray exposure, and short-scanning time.^37,38 In studies that included these imaging techniques and common clinical measurements, the abdominal sagittal diameter was found to be the most specific predictor of visceral adipose volume, but measurements of waist circumference and sagittal diameter are also highly correlated. Even though waist circumference varies considerably between sexes and among different ethnic groups, it has been proposed as a crude, but efficient, anthropomorphic readout for abdominal adiposity.^39,40 And lastly, the amount of visceral fat is correlated to total body fat even though considerable variation in individual fat distribution has been reported,^41-44 Thus, despite the lack of a ”gold standard” for the quantitative assessment of regional fat distribution in humans, most of the evidence suggests a specific association between visceral fat with an increased risk for insulin resistance and diabetes.

TO BE (FAT) OR NOT TO BE

Interestingly, deficiency of fat tissue (lipodystrophy) predisposes to similar metabolic complications as an excess of fat in obesity, such as insulin resistance, T2DM, and hepatic steatosis (reviewed in Refs 45 and 46^45,46). Moreover, fat transplantation into lipodystrophic mice ameliorated the diabetic phenotype of the animals either partially or completely, implicating that the failure to properly store lipids in depots is causal for lipodystrophic diabetes.⁴⁷ Also in normal lean animals, fat transplantation has been shown to result in beneficial metabolic effects.^48,49 Thus, adipose tissue may have both beneficial and adverse effects on whole-body metabolism, depending on where it accumulates.

OBESITY-INDUCED DIABETES: FACTORS AND MECHANISMS

On a population level, the link between obesity and its secondary complications is well described. However, the molecular mechanisms underlying these complications are still poorly understood.⁵⁰ Even though the evidence indicates a detrimental role of visceral fat in terms of insulin sensitivity, relatively little is known about distinct physiological and biochemical properties of fat tissue derived from different anatomic locations. On the one hand, transplantation experiments with fat tissue from different adipose depots in mice have not conclusively revealed intrinsic differences between subcutaneous and visceral fat.^47,49 On the other hand, factors that have been attributed to confer differential metabolic effects of subcutaneous versus visceral fat include increased portal release of FFA and glycerol from omental/mesenteric fat directly to the liver, and also differences in endocrine and metabolic functions of fat depots.

Three main hypotheses have been developed in recent years to bridge the gap between epidemiology and pathobiochemistry:

(1) The “inflammation hypothesis” asserts that obesity represents a state of chronic inflammation where inflammatory molecules produced by infiltrating macrophages in adipose tissue exert pathological changes in insulin-sensitive tissues and β-cells.

(2) The “lipid overflow hypothesis”, also known as “Adipose Tissue Expandability Hypothesis” predicts that obesity may result in increased ‘ectopic’ lipid stores (lipid that accumulates outside the normal depots, such as in the organ tissue of the liver, muscle, and pancreas) due to the limited capacity of adipose tissue to properly store fat in obese subjects. Potentially harmful lipid components and metabolites may exert cytotoxic effects on peripheral cells, including liver and β-cells, thereby impairing function, survival, and regeneration.

(3) The “adipokine hypothesis” refers to the principal feature of white adipose cells to function as an endocrine organ, and to secrete a variety of hormones with auto- and paracrine function. It has been proposed that expanding fat stores in obesity cause dysfunctional secretion of such endocrine factors, thereby resulting in metabolic impairment of insulin target tissues and eventually failure of insulin producing β-cells.

In the following, these three hypotheses are briefly discussed.

The “Inflammation Hypothesis”

Inflammatory processes are thought to play a key role in the development of obesity-related insulin resistance and type 2-diabetes. In adiposity there are fundamental changes in adipose tissue secretory functions⁵¹. An excess of adipose tissue produces a number of pro-inflammatory cytokines leading to a state of chronic subclinical inflammation associated with both insulin resistance and type-2 diabetes.⁵² The term “metaflammation” describes this low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy.⁵³

How does a spill-over of these inflammatory products into circulation finally lead to insulin resistance? Weisberg et al⁵⁴ described that macrophages accumulate in adipose tissue of obese subjects and suggested that these macrophages are derived from the circulation. Further studies indicated that adipose tissue macrophages (ATMs) that accumulate during diet-induced obesity (DIO) are not only an important source of adipose tissue inflammation but also mediate insulin resistance in adipocytes.⁵⁵ The amount of macrophages in adipose tissue correlates positively with two indices of adiposity: Body mass index (BMI) and adipocyte size. The exact mechanisms underlying ATM recruitment and activation are still not fully understood. One factor potentially responsible for obesity-induced inflammation by increasing ATM recruitment is Macrophage Migration Inhibitory Factor (MIF), a chemokine-like inflammatory regulator directly associated with the degree of peripheral insulin resistance.⁵⁶ Adipose tissue macrophages are considered to be a major reservoir of pro-inflammatory molecules in adipose tissue⁵⁴. These cytokines exert various functions in the pathogenesis of the disease progression (Figure 1). Some of the most important inflammatory factors are described below.

Figure 1. The “inflammation hypothesis.” Pathophysiology of obesity-induced chronic inflammation and peripheral insulin resistance.

DAG, diacylglycerol; IL-1, interleukine-1; MCP-1, monocyte chemotactic protein-1; TNF, tumor necrosis factor alpha; Toll-like receptor 4, TLR-4; Details in the text.

The “Lipid Overflow Hypothesis”

Healthy adipose tissue is characterized by the ability to expand passively to accommodate periods of nutrient excess. In contrast, adipose tissue in polygenic mouse models of obesity-induced diabetes, as well as in obese humans, may fail to fully accommodate excessive nutrient loads.^91-93 If the adipose tissue expansion limit is reached, lipids can no longer be stored appropriately in adipose tissue and consequently “overflow” to other peripheral tissues such as skeletal muscle, liver, and pancreas.^94,95 Subcutaneous adipose tissue (SAT) represents the largest adipose tissue depot and, in addition, is considered the least metabolically harmful site for lipid storage. The SAT can expand either by increasing the size of the cells (hypertrophic obesity) and/or by recruiting new cells (hyperplastic obesity). In contrast to the hyperplastic response, which seems to be protective against SAT dysfunction, hypertrophic obesity is associated with increased T2D risk.^96,97 The storage of this ectopic fat in non-SAT tissues is directly linked to the progression of insulin resistance and type-2-diabetes.^98,99 Thus, fat accumulates in tissues that are not adequate for lipid storage, and as a consequence, lipid metabolites might accumulate within those tissues that inhibit insulin signal transduction (Figure 2).

Figure 2: The “lipid overflow hypothesis.” Pathophysiology of obesity-induced ectopic lipid stores that cause peripheral insulin resistance and impaired β-cell function.

CPT-1, carnitine palmitoyltransferase 1; DAG, diacylglycerol; GLUT2, facilitated glucose transporter, member 2 (SLC2A2); HAD, β-hydroxyacyl dehydrogenase; IRS1, insulin receptor substrate 1; MafA, pancreatic beta-cell-specific transcriptional activator MafA; PKC, Protein kinase C; Details in the text.

This hypothesis is supported by several rodent models of lipodystrophy. These animals are extremely lean but often suffer from marked insulin resistance, diabetes, hypertriglyceridemia, hepatosteatosis, and low HDL (high-density lipoprotein)-cholesterol levels – a metabolic profile similar to that observed in obesity-related metabolic syndrome.^100,101 Moreover, recent studies demonstrate a lipodystrophy-like phenotype also in the general human population since subjects who are of normal weight but metabolically unhealthy (∼20% of the normal weight adult population) have a greater than 3-fold higher risk of all-cause mortality and/or cardiovascular events.⁴⁶ Leptin replacement in patients with generalized lipodystrophy can serve as efficient therapy to improve insulin sensitivity by reducing ectopic fat accumulation, especially in the liver.^102-104

Thus, an increased fatty acid flux from normal fat depots towards non-adipose tissues (NAT), e.g. skeletal muscle, heart, liver, and pancreatic β-cells appears to be a critical factor in mediating lipotoxicity. Among the substances known to impair insulin signaling, the most prominent examples include diacylglycerols (DAGs) and ceramides, which have both been shown to impair insulin action in a number of peripheral tissues.^105-107

The “Adipokine Hypothesis”

Adipose tissue is not only a storage compartment for triglycerides but also a major endocrine and secretory organ, which releases a wide range of factors (adipokines) that signal through paracrine and hormonal mechanisms.¹⁴⁴ Some of these secreted molecules are involved in inflammatory processes, such as TNF-α, IL-1β, IL-6 and MCP-1 as described above. The expanding volume of adipose tissue during obesity raises circulating levels of these inflammatory markers and is therefore thought to contribute to insulin resistance¹⁴⁵ and the development of T2DM (Figure 3).

Figure 3: The “adipokine hypothesis.” Pathophysiology of obesity-induced dysfunction of adipokines in adipose cells contributing to peripheral insulin resistance.

AdipoR2, adiponectin receptor 2; AMPK, AMP-activated protein kinase; PEPCK, phosphoenolpyruvate carboxykinase; RBP4, retinol binding protein 4; Details in the text.

More than 100 different factors secreted by adipocytes have been identified over the past years, and it seems likely that this number will increase further due to the progress in analytical chemistry.¹⁴⁶ Some of the prominent members of hormones produced by the adipose tissue are described below.

GENETIC SUSCEPTIBILITY FOR OBESITY AND INSULIN RESISTANCE

summary

Although immune system, ectopic fat, and macro/micronutrients all contribute in part to the susceptibility for diabetes in the obese state, most of the underlying molecular mechanisms are still poorly understood. The identification of susceptibility genes mediating the progression of type 2 diabetes is crucial to prevent the massive epidemics of the disease. Future research will be focused not only on gene-gene interactions but also on the interplay of genetic and environmental risk factors.

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