Which is the most important for the successful management of diabetes mellitus?

Lifestyle management along with pharmacological approaches is crucial to achieve a successful management of diabetes.

Introduction

Insulin resistance and β-cell dysfunction are the 2 major hallmarks of type 2 diabetes mellitus [T2DM] that appear as the result of disturbed homeostasis [1]. Failure of β-cells [∼80% of their β-cell function] and insulin resistance in muscles and the liver is a vicious triumvirate responsible for the core physiological defects. However, T2DM is classically viewed as a disorder of insulin deficiency and resistance, and further insights into the pathophysiology of T2DM suggest the role of other key players in insulin deficiency and its functional inability. Pancreatic islets are composed of insulin-releasing β-cells [48–59%], glucagon-releasing α-cells [33–46%], somatostatin [SsT]-releasing δ-cells, and F cells that release polypeptides [PPs] in similar proportion [2]. Moreover, paracrine interactions occur in the sequence from β-cell to α-cells followed by δ-cells and PP-cells/F-cells [3]. While the β-cell interactions are emphasized at present, the interaction of other cells in pancreas is of crucial importance that needs to be explored further to understand their roles in glucose homeostasis [2]. Also, the development of glucose resistance in T2DM is largely influenced by fat cells [accelerated lipolysis], gastrointestinal tract [incretin deficiency/resistance], α-cells [hyperglucagonemia], kidneys [increased glucose reabsorption] and brain [insulin resistance], and complex interactions that occur between these factors and T2DM associated genes [4]. Changes in the lifestyle of T2DM patients are crucial along with pharmacological interventions to improve the overall health status of the patient. The present review discusses our current understanding of the pathogenesis of T2DM and attempts to emphasize on generally unfocused aspects of T2DM pathogenesis and treatment that may contribute significantly to treatment approaches and patient-related outcomes.

Understanding the Diabetes Machinery: The Unfocused Aspects

Amylin Proteins and Pancreatic β-Cell Function

β-Cells are the most extensively studied pancreatic cells for their roles in glucose homeostasis in T2DM. Islet amyloid PP [amylin] is a β-cell peptide hormone that is secreted along with insulin in the ratio of approximately 100:1. Its secretion is also altered in diabetic patients. Amylin functions as an inhibitor of glucagon secretion and delays gastric emptying thus acting as a satiety agent [5]. Amylin action is executed through an area postrema [glucose-sensitive part of the brain stem] that collectively aims to reduce the demand of total insulin [6]. Besides these functions, amylin also plays roles in the destruction of β-cell via the formation of amyloid aggregates and fibers [7]. Findings from histopathology have shown the accumulation of extracellular amyloid proteins, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein [a], c-Jun N-terminal kinases [JNK1], and islet-brain 1/JNK1 interacting protein-1 [IB1/JIP-1] as the characteristic feature of pancreatic islets in T2DM individuals, suggesting that amylin in association with endocrine system plays important roles in physiology, pathology, and progression of T2DM [8].

α-Cells

α-cells are known to play crucial roles in the pathophysiology of T2DM. The secretion of glucagon from α-cell is regulated by glucose, hormones, and other substrates that work in unison. Any abnormality in α-cells is reflected in altered glucose homeostasis [9]. In T2DM, a relative elevated secretion of glucagon takes place in fasting and postprandial states during normal and increased glucose levels along with altered hypoglycemic response [10]. According to the bi-hormonal hypothesis, T2DM is the consequence of insulin resistance/deficiency with a relative excess glucagon secretion, leading to a rate of hepatic glucose production that is much higher than the rates of glucose utilization. This consequently results in hyperglycemia. The hypothesis is supported by a plethora of clinical and experimental investigations [11, 12]. Reduced suppression of glucagon release under hyperglycemic conditions is a contributing factor to postprandial hyperglycemia [13]. Interestingly, α-cells do not show this behavior in the presence of adequate insulin levels, suggesting that impairment in insulin machinery also cause the abnormalities in glucagon release in T2DM [14]. In addition to this, hypoglycemia is remarkably influenced by glucagon secretion in T2DM patients treated with insulin. In such patients, the secretory response of α-cells to low-glucose concentrations is compromised, which further aggravates the risks of severe hypoglycemia [15]. The deficiency of glucagon action in response to hypoglycemia is linked with multiple failures in α-cell regulation [16]. Even in the situation of islet allotransplantation that helps diabetes patients to remain independent to insulin for a long time, the retarded response of α-cell response to hypoglycemia usually remains unaffected, indicating that the procedure does not completely restore the physiological functions of α-cells [17]. Collectively, defects in α-cell regulation and glucagon secretion lead to defective glucose sensing, loss of β-cell function, and insulin resistance.

δ-Cells, SsT, and Pancreatic PP Cells [F-Cells]

The δ-cells are located in the stomach, intestine, neuroendocrine cells, and pancreas. They secrete SsT in a pulsatile manner in response to fluctuations in glucose levels [18]. SsT regulates the endocrine functions and also plays an important role in the gut-brain axis. The receptors of SsT are present on α- and β-cells where they act as inhibitory receptors for the secretion of insulin and glucagon. SsT exerts a tonic inhibitory effect on the secretion of insulin and glucagon and facilitates the islet response to cholinergic activation. In addition, SsT is also involved in the suppression of nutrient-induced glucagon secretion [19]. Further, SsT significantly alters the normal glucose homeostasis and feedback loops [20].

F-cells of the pancreas release pancreatic PP after the food intake. It exerts inhibitory postprandial effects on gastric emptying, intestinal motility, exocrine pancreatic secretion, hepatic glucose production, and gallbladder contraction. Functional abilities of PP significantly affect food intake and energy metabolism [21]. When administered through intracerebroventricular route, PP exerts an orexigenic [appetite stimulating] effect in the brain. On contrary, intraperitoneal administration of PP reduces the food intake and lowers body weight by enhancing energy expenditure [22, 23]. Increased plasma levels of PP are implicated in obesity and diabetes.

Adipose Tissue and Resistin

Adipose tissue consists of adipocytes, connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. The role of adipose tissue as an endocrine organ is well established [24]. It releases leptin, cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Apart from secreting factors/hormones, adipose tissue also functions in coordination with other hormone systems and the central nervous system. Typically, adipose tissues serve as a store house for fat under normal conditions, while they also release free fatty acids [FFAs] in metabolic disorders. Consistent decline in the function of β-cell in normal individuals has been shown to be associated with progressive secretion of FFAs and insulin resistance in adipose tissue [25]. Resistin or adipose tissue-specific secretory factor released from adipose tissue is largely implicated in the progression and development of T2DM [24]. It acts as an inhibitory hormone that causes resistance to insulin [26]. Levels of circulating resistin increase in T2DM, resulting in oxidative stress, insulin resistance, and platelet activation [27]. Expression of the resistin gene is also observed in the pancreatic islets, pituitary, and hypothalamus [28]. Although resistin is primarily secreted by macrophages in humans [29] where it is involved in the recruitment of immune cells and pro-inflammatory factors, the involvement of resistin is also seen in hyperglycemia and insulin resistance [30, 31]. Resistin-induced hyperglycemia and obesity are induced through the activation of AMP-protein kinase and decreased expression of gluconeogenic enzymes in the liver. Induction of insulin resistance is also evident in rodents after the administration of recombinant resistin that reverses with the immune neutralization [32].

Genetics

T2DM is notorious for being “the geneticist’s nightmare.” Occurring due to the combined contribution of genetic and environmental factors, leading to multiple gene alterations [33]. Multiple mechanisms act either directly or in association with other factors to influence the development and progression of T2DM. These include defects in pancreatic angiogenesis, innervation, and modification of parental imprinting [34]. The pathogenesis of T2DM depends on the intensity of both maternal and paternal insulin resistivity and/or insulin sensitivity [35]. According to one study, the first-degree relatives of T2DM patients live at a higher risk of developing T2DM and have a strong genetic predisposition to β-cell failure [36]. Moreover, β-cell dysfunction, autosomal dominance, and heterozygous mutations in β-cell transcription factors are some of the major causes leading to early onset of T2DM. The identified genes responsible for the early-onset T2DM include insulin promoter factor-1, hepatocyte nuclear factor [HNF]-4α, NeuroD1/BETA2, HNF-1α, and HNF-1β [37]. A hyperglycemic intrauterine environment has also been implicated in T2DM or pre-diabetes in the offspring of women suffering from gestational diabetes [38]. Also, during gestational diabetes, the expression of insulin receptor-β, PI3K [phosphatidylinositol 3-kinase] with its subunit p85α and GLUT-4 decreases with a compensatory elevation in the expression of GLUT-1 mRNA in placental tissues [39]. Polymorphism in resistin gene 299 [G>A] and increase in serum resistin is also known to be a contributing factor to increased insulin resistance with a subsequent higher risk of T2DM in offspring. Moreover, offspring carrying AA and combined GA + AA genotypes tend to be at higher risk [40]. On the other hand, diabetes also has the capacity to make genetic alterations leading to associated comorbidities. For instance, alterations in genes involved in vitamin synthesis leads to lowering of levels of riboflavin and glycemia, microalbumineria, and altered levels of uric acid in T2DM individuals and development of insulin resistance due to vitamin D deficiency [41-46]. Importantly, the genes of vitamin D receptor and its binding protein along with CYP1α show polymorphisms in diabetics [42-44].

Gut

The gut serves as a prominent link between the brain and the enteric nervous system [47]. The secretion of gastrointestinal hormones [incretin, glucagon-like peptide-1 [GLP-1], and glucose-dependent insulinotropic polypeptide [GIP]] increases after food intake. These hormones assist insulin and glucagon in maintaining glucose homeostasis and improve α-cell glucose sensing. GLP-1 promotes assimilation of ingested nutrients through glucose-stimulated insulin secretion and evidently improves β-cell sensitivity to glucose [48]. Moreover, GLP-1 also suppresses glucose-dependent glucagon secretion, retards gastric emptying, and promotes satiety [49]. In the pancreas, β-cell proliferation and inhibition of apoptosis are promoted by GIP and GLP-1 that ultimately expand pancreatic β-cell mass. In addition, fat deposition is also facilitated by GIP. In the brain, GIP and GLP-1 are involved in appetite control. GIP also decreases gastric acid secretion, while GLP-1 decreases the duration of gastric emptying. Moreover, the insulinotropic effects of GIP and GLP-1 differ in T2DM patients such that GLP-1 secretion is impaired, while the secretion of GIP remains unaffected [50]. Alterations in incretin functioning and the associated pathways result in increased gastrointestinal permeability in T2DM and form one of the basic underlying mechanisms responsible for diabetic comorbidities in the latter phase [48, 49, 51].

The gut also releases other hormones which are involved in multiple signaling cascades. These include [but not limited to] ghrelin, galanin, cholecystokinin [CCK or pancreozymin] and leptin [52]. The enteroendocrine cells [I cells of the duodenum and jejunum] and neurons synthesize and release CCK in response to meals and induce pancreatic acinar cells to secrete pancreatic digestive enzymes. CCK also reduces gastric emptying and enhances the digestion process [53]. Vagus stimulation causes trypsin release from pancreas that hydrolyzes CCK to maintain homeostasis through the feedback mechanism. CCK is positively associated with leptin and insulin levels resulting in disrupted glucose homeostasis and diabetic complications in T2DM [53, 54].

Gut Microbiota

Diabetes is considered as a disease of the intestine where gut microbiota plays a crucial role [55, 56]. The concentration of microflora distally increases along the length of the gastrointestinal tract [57]. The flora of the upper intestine generally accounts for