Review
Obesity and diabetes: An update

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Abstract

The twin epidemic of obesity and diabetes is a major crisis globally. Several epidemiologic studies reveal the parallel escalation of obesity and diabetes. The term ‘diabesity’ expresses their close relationship to each other, wherein both these metabolic disorders are characterized by defects of insulin action. The pathophysiology connecting obesity and diabetes is chiefly attributed to two factors: insulin resistance and insulin deficiency. Recent years have seen an increasing body of work on the following metabolic defects common to both obesity and diabetes such as, impaired tissue perfusion, sleep disturbances, androgen dysfunction, altered Vitamin D levels and GI stress. The scope of this review is to present the most widely accepted theories that link the two diseases, provide an update on some proposed unifying metabolic defects and highlight current and future prevention and management strategies.

Introduction

The twin epidemic of obesity and diabetes is a major crisis globally. Several epidemiologic studies reveal the parallel escalation of obesity and diabetes. The term ‘diabesity’ expresses their close relationship to each other, wherein both these metabolic disorders are characterized by defects of insulin action [1]. Diabetes is a global health care problem that threatens to reach pandemic levels by 2030. As of 2014, there are 387 million people living with diabetes, worldwide. Moreover, around 316 million with impaired glucose tolerance are at high risk from the disease, a number that is set to reach 471 million by 2035. Without concerted action to prevent diabetes, it is projected that around 592 million people will be living with the disease in another 25 years’ time [2]. Further, Type 2 diabetes mellitus (T2DM) represents approximately 90% of all cases of diabetes, and its frequency is similar to that of obesity [3].

Recent estimates indicate that obesity currently affects more than 600 million people worldwide and is associated with more than 45 comorbidities, in addition to several atherogenic disorders that compose the metabolic syndrome [1]. On account of established health risks and substantial increase in prevalence, obesity has become a serious global health problem. The burden of obesity is particularly high in the middle-income countries of Eastern Europe, Latin America and Asia where it is the fifth most common cause of disease burden, ranking just below underweight [4]. Developing countries have shown a steep rise in obesity rates over the last two decades, owing to adoption of a Western lifestyle, which has resulted in profound changes in the quality, quantity and sources of food consumed, compounded by the effects of decreased physical activity. While increase in obesity in developed countries, which began in the 1980s and accelerated from 1992 to 2002, has slowed since 2006, the increase is likely to continue in developing countries, where almost two-thirds of the world’s obese population currently resides [5].

The scope of this review is to present the most widely accepted theories that link the two diseases, provide an update on some proposed unifying metabolic defects and highlight current and future prevention and management strategies.

The increase in the prevalence of type 2 diabetes is closely linked to the upsurge in obesity. It is estimated that about 90% of T2DM is attributable to excess weight [4]. The pathophysiology connecting obesity and diabetes is chiefly attributed to two factors: insulin resistance and insulin deficiency [6] (Fig. 1). Obesity causes sustained elevation in plasma FFA levels, both in the basal state and following glucose load which present a major factor for insulin resistance [7], [8]. Source of the FFA excess in obese individuals are considered the meal-derived fatty acids and lipolysis of the adipose tissue [1]. Furthermore, central-abdominal fat is metabolically and lipolytically more active, releasing more FFAs in the bloodstream [9]. Clinical studies in healthy volunteers with acute elevation of plasma FFAs resulted in whole body insulin resistance [10]. Increased plasma FFAs by mass action augment their cellular uptake and induce their mitochondrial β-oxidation, blocking at the level of substrate competition, intermediates accumulation, enzyme regulation, intracellular signaling and/or gene transcription the glucose metabolism [1]. The predominant utilization of lipids at the expense of glucose, shown by the increase in lipid oxidation induces a diminution of glucose uptake by muscle and decreased rates of glycogen synthesis in skeletal muscle [11], [12], [13]. This state of chronic hyperglycemia (glucotoxicity) further impairs insulin sensitivity. Hyperglycemia and compensatory hyperinsulinemia associated with insulin resistance and glucose intolerance lead to pathological glycation of circulating proteins and formation of advanced glycation end products. This progression ultimately leads to a pancreatic beta cell secretory failure and apoptosis.

Ravussin et al. [14] showed that when the diet-derived fat intake is increased, fat storage within and around other tissues and organs including liver, skeletal muscle and pancreatic β-cells, which under normal conditions do not store lipids, takes place. This in turn results in excessive mitochondrial production of toxic reactive lipid species that cause organ-specific oxidative damage and cellular dysfunction, leading progressively to the development of insulin resistance, impaired glucose metabolism and finally to diabetes [15]. The accumulation of toxic metabolites within the pancreatic islet β-cells in particular affects insulin secretion and enhances β-cell apoptosis accelerating the progression to overt diabetes [1]. At the cellular level, the progression from insulin resistance to diabetes is accompanied by oxidative stress and systemic inflammation. Increasing evidence suggests that chronic low-grade inflammation in adipose tissue affects the pathogenesis of diabetes in obese patients [16]. (Table 1 enumerates major biomarkers contributing to inflammation in obesity and diabetes). Obesity induces inflammation via LPS-related endotoxemia involving gut microbiota [3]. Inflammation is characterized by an upsurge of T-lymphocytes and M1 macrophages which have increased secretion of proinflammatory cytokines that act to perpetuate systemic inflammation and induce insulin resistance [3]. In addition, inflammatory signals associated with obesity compromise endoplasmic reticulum function and result in marked JNK activation in insulin-sensitive tissues, such as fat and liver. Activated JNK, specifically the JNK1 isoform, play a dominant role in insulin receptor substrate-1 serine phosphorylation and subsequent inhibition of insulin action [17].

Recent years have seen an increasing body of work on the following metabolic defects common to both obesity and diabetes:

  • Impaired tissue perfusion

  • Sleep disturbances

  • Androgen dysfunction

  • Altered Vitamin D levels

  • Gastrointestinal stress

A vicious circle of progressive microvascular dysfunction both contributes to and is exacerbated by worsening insulin resistance. Capillary recruitment is an important mechanism by which insulin promotes uptake of glucose from the blood [19]. Impaired recruitment and rarefaction may, therefore, reduce glucose uptake and contribute to insulin resistance [20]. There is considerable evidence to suggest that insulin resistance and hyperglycemia, acting via oxidative stress, inflammation, and advanced glycation end products, can induce microvascular abnormality [21] causing increased microvascular permeability in diabetes [22]. Several studies have shown impaired coronary flow reserve in diabetic individuals in the absence of coronary artery stenosis [23], [24], [25], [26]. An inverse relation between hyperemic myocardial blood flow and fasting insulin level has also been found among healthy, nonobese individuals, which suggests that even mild insulin resistance is associated with impaired coronary flow reserve [27].

Microvascular function is found to be negatively correlated with adiposity [28]. Proposed mechanisms include:

  • a)

    Obesity associated oxidative stress and reduced nitric oxide availability as important mechanisms in the development of microvascular rarefaction [29].

  • b)

    Excess adiposity is associated with a chronic state of vascular inflammation, with increased levels of proinflammatory cytokines, particularly, production of tumor necrosis factor (TNF), which is negatively correlated with skin capillary recruitment and insulin sensitivity [30]. Deposits of fat around arterioles may be involved in local TNF- signaling and consequently impaired perfusion and insulin resistance [31].

  • c)

    Increased fat mass leading to prolonged elevation of free fatty acid levels in the blood, which can impair capillary recruitment [32].

Epidemiological studies have established the association of short sleep with an increased prevalence of type 2 Diabetes and obesity [33], [34], [35], [36], [37], [38], [39]. The cross-sectional observations of lower leptin and higher ghrelin concentrations in decreased sleep duration, independent of BMI, have led to hypothesizing that such hormonal changes promote overeating and lead to increased risk of obesity [40], [41]. Furthermore, BMI was found to be inversely proportional to sleep duration in persons sleeping <8 h [40].

Experimental studies have demonstrated a decrease in glucose tolerance as a result of partial sleep deprivation [42]. Additionally, partial sleep restriction caused a reduction in leptin, elevation in ghrelin and an increase in hunger and appetite ratings with preference for calorie-dense higher carbohydrate content food when caloric intake was kept constant [43]. It also resulted in impaired insulin signaling in abdominal fat tissue with a concurrent decrease in whole body insulin sensitivity [44]. Sleep restriction to 4 h compared to 8.5 h time in bed resulted in increased endogenous glucose production, indicating hepatic insulin resistance [45] and decreased glucose disposal rate reflecting decreased peripheral insulin sensitivity. Prolonged partial sleep restriction could also contribute to obesity and diabetes by the means of chronic, low-grade inflammation as shown by an increase in the level of proinflammatory cytokines and altered immune [46] and stress responses resulting from the loss of sleep [47].

There is a bidirectional modulation of glucose homeostasis by androgens in males and females. Androgen deficiency in males and androgen excess in females produce metabolic dysfunction via deficient or excessive androgen-receptor (AR) action, respectively, in multiple tissues including the central nervous system, liver, skeletal muscle, adipose and β-cells [48].

Males exhibit an inverse correlation between total serum testosterone and the amount of visceral adipose tissue [49]. Testosterone action prevents fat accumulation in males via a combination of Estradiol-receptor and androgen-receptor mediated effects. Several studies suggest that the suppressing effect of testosterone on white adipose tissue tissue is indirectly mediated via AR signaling in skeletal muscle that (a) Stimulates the commitment of pluripotent mesenchymal stem cells into myogenic lineage while at the same time suppressing the adipogenic lineage [50] and (b) Indirectly decrease adipose tissue mass by increasing muscle oxidative metabolism [51]. Low testosterone levels are associated with low PGC1 expression [52], a molecular marker of muscle insulin sensitivity that stimulates mitochondrial biogenesis and skeletal muscle oxidative fibres [51].

In women, however, hyperandrogenism predisposes to T2DM. Higher levels of free testosterone and low concentration of sex-hormone binding globulin (SHBG)-which increases free testosterone, have been repeatedly associated with glucose intolerance and insulin resistance in women [53], [54], [55], [56], [57]. High testosterone levels produce insulin resistance by decreasing insulin stimulated whole body glucose uptake in healthy pre- and postmenopausal women [54], [58], [59], [60]. Moreover, this reduced insulin stimulated whole body glucose uptake was not attributable to hepatic insulin resistance, which remained unchanged, supporting a role for skeletal muscle in insulin resistance [58]. Role of excess testosterone in promoting skeletal muscle insulin resistance with fiber type switch has also been confirmed in studies [61], [62]. Generally, insulin sensitivity is shown to be improved when hyperandrogenism is reversed with anti-androgen therapy, in association with weight loss [63], [64], [65]. Androgen excess also prevents leptin from activating brown adipose tissue thermogenesis, which is associated with reduced energy expenditure and visceral obesity [48]. Summarily, in women with a prior β-cell defect, excess testosterone may increase predisposition to β- cell failure through the cumulative action of various β-cell stresses, including insulin resistance and circulating oxidative stress [58].

There is evidence that vitamin D acts at multiple sites to inhibit fat accumulation, increase insulin synthesis and preserve pancreatic islet cells, decrease insulin resistance and reduce hunger, favoring obesity and T2DM control [66].

In adipocytes, vitamin D appears to inhibit the active form of adipogenic transcription factors and fat accumulation during the differentiation phase [67]. Additionally, since there are VDREs in the insulin promoter genes [68], it is proposed that vitamin D modulates insulin synthesis in the β-pancreatic cells, mediated by nVDR. Vitamin D may also promote morphological improvements in pancreatic islet cells, decrease apoptosis, and have nongenomic effects via the mVDR [69]. In skeletal muscle, there is evidence that vitamin D can decrease insulin resistance and increase glucose uptake [70]. Moreover, decreased levels of serum vitamin D can reduce circulating calcium and induce secondary hyperparathyroidism [71]. The parathormone (PTH) chronically increases intracellular levels of ionic calcium in adipocytes, which may act reciprocally on increased expression of fatty acid synthase (FAS)—a key regulatory enzyme in the deposition of lipids—and on decreased lipolysis. Also, decreased thermogenesis and lipid oxidation through the down-regulation of uncoupling proteins have been suggested [72]. Thus, an increase in PTH may induce weight gain, obesity, and T2DM. Other targets of vitamin D action are immune cells where it reduces the hypersecretion of chemokines and cytokines in monocytes [73], and control functions, maturation and/or growth of T cells [74], B cells [75] and dendritic cells [76], to generate a more tolerant and anti-inflammatory response profile.

Incretins, are gut-derived hormones released predominantly by the L cells in the distal bowel in response to a meal [77]. They work by enhancing the insulin release from pancreatic beta cells and inhibiting postprandial glucagon secretion and gastric emptying after a meal [78] bringing about a reduction in blood sugar concentrations. Ghrelin, a peptide produced by the stomach, stimulates appetite and has a pro-diabetic role, causing hyperglycemia through inhibition of insulin resistance and stimulation of release of counter-regulatory hormones, and impairing insulin sensitivity [79]. Its levels increase with fasting and decrease after a meal [80]. Another peptide Obestatin, derived from ghrelin precursor but with opposite effects has recently been found to be produced by the same neuroendocrine cells that secrete the orexigenic hormone. It counterbalances the effects of ghrelin by decreasing appetite [81].

Studies have consistently shown the association between obesity and unbalanced dominant gut phyla, with reductions in Bacteroidetes and a proportional increase in Firmicutes [82], [83], [84], [85], [86], [87]. Obesity is closely related to endotoxemia because of the increased intestinal permeability [88]. It has been proposed that high fat diets by means of reducing the expression of tight junction proteins and modulating the gut microbiota, increase the intestinal permeability leading to metabolic endotoxemia associated with increases in inflammatory tone, body weight gain, and insulin resistance [88].

The mainstay for the prevention, amelioration and treatment of obesity and the associated insulin resistance constitute strategies that reduce fat mass. Lifestyle modifications such as controlled caloric intake, healthy diet and increased physical activity remain the first line treatment, while anti-obesity drugs (orlistat, siutramine) and bariatric surgery work additionally for loss of the excessive body weight.

The first T2DM therapeutics to target the beta cells was the sulfonylurea compounds, which act directly on the ATP-sensitive potassium channels of the beta cell to enhance membrane depolarization, stimulating exocytosis of insulin granules [89]. However, sulfonylureas act in a glucose-independent manner, increasing the potential risk of hypoglycemia [90]. Furthermore, sulfonylureas and other long established therapeutics, including the insulin-sensitizer metformin, do not prevent the continuing loss of beta cell function observed in T2DM [91]. Incretin-based therapies are increasingly being used in clinical practice for the management of T2DM [92], [93] that address a different aspect of beta cell dysfunction: the lack of potentiation of insulin secretion in response to an oral glucose/nutrient challenge [94]. This potentiation occurs because of incretins that act on the pancreas and other peripheral tissues to elicit biological effects, including augmenting nutrient-stimulated insulin secretion. This effect of incretins is lost or blunted in T2DM [95]. Therapeutic approaches for enhancing incretin action include degradation-resistant Glucagon-like Peptide 1 (GLP-1) receptor agonists (incretin mimetics) and inhibitors of Dipeptidyl Peptidase 4 (DPP-4) activity (incretin enhancers) [92]. In addition to their incretin effect, they exert a glucose-lowering effect with no or only a minimal risk of hypoglycaemia [92], [96]. Moreover, DPP-4 inhibitors are weight-neutral, whereas GLP-1 receptor agonists reduce body weight [92].

Several novel medications that target specific molecules and biochemical pathways implicated in the pathogenesis of insulin resistance including glucocorticoid receptor inhibitors and factors that reverse endoplasmic reticulum stress and restore it, promise more effective treatment of insulin resistance in the future. Finan [97] and colleagues have reported the discovery of a new agonist that simultaneously targets three key metabolically related peptide hormone receptors—the receptors for glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon. This unimolecular triagonist was proved to be remarkably effective at reducing body weight, improving glucose control and reversing hepatic steatosis. Recent studies on the administration of nutritional supplements (e.g. chromium, magnesium, vitamin D) and probiotics that alter gut flora to ‘lean’ type for the amelioration of insulin resistance and diabetes have gained many supporters. Similarly do the centrally acting insulin sensitizers including leptin and dopamine D2 receptor agonists [1]. Their role however in clinical practice remains to be proved.

The effects of physical activity in improving metabolic profile in obesity and diabetes have been unequivocal. Studies have consistently shown improved glycemic control [98], [99], [100], [101], [102], [103], lipid profile [100], [101], cardiovascular fitness [101], [104], [105], [106], antioxidant status [107], [108], quality of life [109], [110], [111] and reduced inflammatory markers [108], [112], [113], [114], [115], [116], adiposity [103], [117], [118], [119], [120] and atherogenic progression [113], establishing physical activity as an evidence-based treatment modality to combat diabesity. The joint position statement of ACSM and ADA [121] recommends undertaking exercise as a safe and effective measure for diabetes management and prescribes the following dose. Aerobic training to be performed at least 3 days/week with no more than 2 consecutive days between activity bouts, at a moderate intensity (40–60% VO2 max) for a minimum of 150 min/week. Resistance training should be undertaken at least twice weekly on non-consecutive days, at a moderate intensity of 50% of 1 RM involving 10–15 repetitions for the major muscle groups (in the upper body, lower body and core). The position stand of ACSM on physical activity intervention strategies for weight management [122] provide evidence for the prevention of weight gain, promotion of clinically significant weight loss and also prevention of weight regain after weight loss with doses that approximate 250–300 min/wk (approximately 2000 kcal/wk) of moderate intensity exercise.

Section snippets

Conclusion

A significant predisposition to insulin resistance is observed with obesity. This review, by no means exhaustive, summarizes the pathogenesis, mediated and influenced by a host of common denominators including: adipokines, immune cells, hormones, Vitamin D, tissue perfusion and sleep. Finally, combating the twin epidemic requires a comprehensive approach including dietary modifications and regular physical activity, augmented by newer pharmaceutical options.

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