How does diabetes cause the 3 Ps?

Abstract

The pathophysiology of diabetes is related to the levels of insulin within the body, and the body’s ability to utilize insulin. There is a total lack of insulin in type 1 diabetes, while in type 2 diabetes, the peripheral tissues resist the effects of insulin. Normally, the pancreatic beta cells release insulin due to increased blood glucose concentrations. The brain in order for normal functions to occur continually requires glucose. Hypoglycemia, or low plasma glucose levels, is usually caused by drugs used in the treatment of diabetes, including insulin and oral antihyperglycemics. The pathophysiology of diabetes involves plasm concentrations of glucose signaling the central nervous system to mobilize energy reserves. It is based on cerebral blood flow and tissue integrity, arterial plasma glucose, the speed that plasma glucose concentrations fall, and other available metabolic fuels. Low plasma glucose causes a surge in autonomic activity. Diagnosis of hypoglycemia requires verification of low plasma glucose levels. Immediate treatment is the intake of glucose. The responses to hypoglycemia include decreased insulin secretion, increased secretion of glucose counter-regulatory hormones such as glucagon and epinephrine, a greater sympathoadrenal response, related symptoms, and finally, cognitive dysfunction, seizures, or coma.

Late hypoglycemia of occult diabetes may develop in some patients with impaired glucose tolerance, or early type 1 or type 2 diabetes. After a high-carbohydrate meal, the patient experiences hypoglycemia.

Pathophysiology

The pathophysiology of diabetes is complex and involves several different hormones (i.e., insulin, glucagons, and growth). The interaction of these hormones with the liver and their involvement in renal function make the pathological mechanisms of this disease difficult to pinpoint and widely varied among patients. More extensive reviews of this pathophysiology can be found on the American Diabetes Association Web site and in medical pathology texts.7,14 Regardless of the cause of diabetes, the result is a decrease in the uptake of glucose. Insulin resistance is mediated by genetic predisposing factors and abdominal obesity.6,17 A strong relationship has been noted between the development of type 2 diabetes and obesity. Eighty percent of type 2 diabetic patients are obese, and excess fat is usually carried in upper body areas.18 The therapist should recognize that medical interventions are directed at achieving normal or near-normal glucose levels and at optimizing lipid values. Interventions vary, depending on the degree of control required and the level of insulin resistance and/or insufficiency noted.2,4 Resultant exercise interventions and expected outcomes vary just as widely. These variations are discussed in the “Interventions” and “Outcomes” sections of the following case.

Introduction

The pathophysiology of diabetes is discussed in other chapters; the etiology of diabetes involves a combination of genetic, lifestyle, and environmental factors. “Environmental factor” is a broad term that could encompass anything from dietary components to chemical exposures; here the focus will be on environmental pollutants or contaminants. Various pollutants have been linked to a spectrum of diseases from asthma to certain cancers. There is evidence in the form of basic science research, animal models, and epidemiologic studies that environmental contaminants may play a role in the development of diabetes. We will focus on epidemiologic evidence linking certain environmental contaminants to diabetes.

Human studies of environmental contaminants are always observational and focus on long-term or acute high-level exposures; or chronic low-level exposures as found in the general population. Since randomized studies are not feasible, the majority of the epidemiologic studies of environmental contaminants and diabetes are cross-sectional with some longitudinal research. Since it would not be possible to include every environmental contaminant in this chapter, several have been chosen that are representative of the current evidence.

Dioxins, furans, polychlorinated biphenyls (PCBs) and some pesticides are part of a group of chemicals known as persistent organic pollutants (POPs). These chemicals are environmentally persistent; although many are now either banned or their production tightly regulated, they will be present in the environment for decades to come. These compounds are some of the most widely studied in terms of health effects from environmental exposures and there is an extensive body of evidence examining the link to diabetes. Pesticides are some of the most widely applied chemicals produced by humans and exposure is essentially universal either from ingestion of treated foods or from other environmental sources. Bisphenol-A or BPA is included as there has been widely publicized debate recently about the potential health effects from this chemical that is used in a variety of everyday products. Air pollution and toxic metals are also included to demonstrate the diversity of compounds studied to determine their role in the development of diabetes.

This chapter should not be considered to be a systematic review of each contaminant described; rather studies that are representative of the current evidence will be presented as an overview to this complex area of research. For some pollutants comprehensive reviews have been published recently; articles published after those reviews are noted in those cases.

YY1 and the insulin signaling genes

The pathophysiology of diabetes is highly dependent on insulin resistance, and many studies have investigated the environmental and genetic factors that propagate T2DM. A recent study has implicated YY1 as a TF that mediates the inhibition of insulin/IGF signaling [51]. This study uses rapamycin, a drug used in cancer therapies and organ transplantation to prevent rejection. Rapamycin was used to induce diabetic-like symptoms and to investigate the mechanism behind these diabetic-like symptoms. It functions by inhibiting mTOR, a serine/threonine protein kinase that regulates cell survival and protein synthesis, by changing mTOR’s conformation, which in turn prevents substrate binding. The study found that inhibition of mTOR through rapamycin causes insulin/IGF signaling defects by suppressing key genes in the signaling pathway, such as Igf1-2, Irs1-2, and Akt1-3. The study also observed a hyperactivation of the insulin/IGF signaling pathway when YY1 was specifically knocked out in the skeletal muscle [51]. Using coimmunoprecipitation and western blot analyses, the study found that YY1 acts as a transcriptional repressor of insulin signaling genes. The pathway begins as follows: mTOR regulates the interaction between YY1 and the polycomb protein Pc2. When mTORC1 is activated, it phosphorylates YY1, disrupting its interaction with Pc2. As a result, YY1 does not bind to the insulin/IGF signaling genes, enabling the transcription activator complex (TAC) to bind and activate the insulin gene transcription (see Fig. 6A). However, when mTORC1 is inactive, YY1 is not phosphorylated, which allows it to maintain its interaction with Pc2. Additionally, YY1 also physically interacts with Ezh2 and PCR2 at the promoters of insulin/IGF, recruiting chromatin modifiers, thus initiating H3K27 trimethylation [51]. This promotes histone acetylation and thus prevents the TAC from binding, thereby inhibiting insulin gene transcription (see Fig. 6B). Hence, this study suggests the possible role of YY1 in T2DM pathophysiology through its role in mediating insulin/IGF signaling. However, further investigations should still be conducted to identify YY1’s role independent of rapamycin.

Furtheromre, Han et al. [52] showed that YY1 physically interacted with PPARγ in mouse adipose tissue. YY1 negatively regulates the transcription and subsequent differentiation of adipocyte tissues. Initially, YY1 binds to the PPARγ promoter. During the early stages of differentiation, the low YY1 expression triggers adipocyte differentiation by physically interacting with C/EBPβ and enhancing its activation as well as repressing the PPARγ promoter, thereby allowing C/EBPβ to bind to the PPARγ promoter [52]. These interactions ultimately facilitate adipocyte differentiation. Since PPARγ is important in lowering blood glucose levels, it can be implied that YY1 indirectly controls blood glucose level. To illustrate, higher YY1 expression will decrease PPARγ expression, which indirectly will increase glucose level. This suggests that YY1 can potentially be a therapeutic target in T2DM patients.

Abstract

With greater understanding of the pathophysiology of diabetes mellitus, the treatment options for patients with type 2 diabetes have expanded. It is therefore important to individualize treatment in each patient for both intensive lifestyle modification and antidiabetic agents. Each antidiabetic agent addresses a specific underlying pathophysiology and carries specific contraindications and side effects. It is important to take into consideration the glycemic goal, risk of hypoglycemia, life expectancy, resources, social support, and comorbidities when making a shared-decision with the patients on the antidiabetic agent. Management of obesity is important as obesity is one of the major risk factor for type 2 diabetes. Treatment of diabetes must also address other cardiovascular risk factors (i.e., hypertension and dyslipidemia) to reduce cardiovascular events and mortality.

5.2 Mitochondrial dysfunction

Mitochondrial dysfunction is indicated in the pathophysiology of diabetes and AD,115,132,133 possibly due to damage caused by oxidative stress.134 Altered insulin signaling was found to reduce the ability of mitochondria to store Ca2 + in diabetic rats.135 The Ca2 + storage potential of mitochondria is critical in maintaining the calcium homeostasis, which is essential for normal neuronal function.136,137 In addition, the “calcium hypothesis” proposes that dysfunction of calcium regulation plays a central role in the development of neurodegenerative diseases.138–142 One hypothesis for the link between insulin resistance, oxidative stress, and cognitive dysfunction is that hyperglycemia due to peripheral insulin resistance induces high levels of mitochondrial oxidative phosphorylation. This in turn leads to overproduction of ROS in the mitochondria and thus structurally damages the mitochondria leading to neurodegenerative cognitive impairment.122,133

A CENTRAL NERVOUS SYSTEM CHANNELOPATHY IN DIABETES?

The role of the CNS in the pathophysiology of diabetes remains incompletely understood. There is some evidence suggesting that prolonged elevated levels of vasopressin, which is produced within the magnocellular neurons of the hypothalamic supraoptic nucleus, are a risk factor for the development of diabetic nephropathy, which can lead to end-stage renal disease (Bardoux et al., 1999; Ahloulay et al., 1999). As noted previously, vasopressin is released as a result of action potential firing by supraoptic magnocellular neurons. Because changes in the transcription of sodium channel genes can be evoked within supraoptic magnocellular neurons by elevations in osmolality within the normal brain (Tanaka et al., 1999), as described at the beginning of this chapter, Klein et al. (2002) recently hypothesized that the hyperosmolality associated with diabetic hyperglycemia can trigger a change in sodium channel expression in these cells. To test this hypothesis, they used in situ hybridization, immunocytochemistry, and patch clamp recording to study sodium channel expression within magnocellular neurons from the hypothalamus of rats with STZ-induced diabetes. As shown in Figure 19.13, in situ hybridization and immunocytochemical analysis demonstrated significant up-regulation of Nav1.2 and Nav1.6 sodium channel mRNA and protein in the magnocellular neurons within weeks of the development of hyperglycemia, but there was no change in sodium channel expression within other nearby nuclei or the surrounding neuropil. To determine whether the upregulated mRNA and protein resulted in the insertion of functional channels within the membranes of magnocellular neu rons, acutely dissociated magnocellular neurons were studied using patch clamp. Although the voltage-dependence of activation and steady-state inactivation (Figure 19.14) and the time constants for inactivation were similar for diabetic and control neurons, the peak transient current amplitude was 130% greater (P < .001) in diabetic magnocellular neurons; peak current density in diabetic neurons was 65% greater (P < .05) than that in controls. Persistent sodium currents, which are known to contribute to neuronal bursting and are increased in magnocellular neurons exposed to hyperosmolar conditions (Tanaka et al., 1999), were also compared. Tetrodotoxin-sensitive persistent currents that were activated at potentials close to threshold (–65 to –55mV) were significantly larger in diabetic neurons, with a current density that was increased by approximately 50% compared to that in control neurons (P < .05; Klein et al., 2002).

This study demonstrates that, in experimental diabetes, increased transcription results in an increased density of functional sodium channels within magnocellular neurosecretory neurons of the hypothalamus, a change that will increase excitability of these cells and evoke vasopressin release from them. Because prolonged elevation of serum vasopressin levels, which increases blood pressure and increases filtration demand to the kidneys, is a factor that leads to the development of diabetic nephropathy (Bardoux et al., 1999; Ahloulay et al., 1999), Klein et al., (2002) hypothesized that the changes in sodium channel expression within the supraoptic nucleus may contribute in a long-term manner to the pathogenesis of diabetic nephropathy. If this speculation is correct, altered sodium channel expression within supraoptic neurons associated with diabetes may be viewed as a channelopathy and may be amenable to therapeutic approaches that might delay the development of end-organ complications such as nephropathy. On the other hand, it is possible that the changes are adaptive, contributing to homeostatic mechanisms in untreated or undertreated diabetes. Further study is clearly needed. Irrespective of whether the changes are maladaptive or adaptive, the changes in the diabetic hypothalamus provide another example of the dynamic nature of ion channel expression within the CNS.

Insulin Resistance

Insulin resistance plays an important role in the pathophysiology of DM and CVD, and both genetic and environmental factors facilitate its development. Insulin resistance is a characteristic feature of T2DM but is also a consistent finding in patients with T1DM (Yki-Jarvinen and Koivisto, 1986; Cleland et al., 2013). Epidemiological evidence strongly associates insulin resistance with CV risk in humans (Rodriguez et al., 1999; Howard et al., 1996; Ferrannini et al., 2007; Wilson et al., 1998). Insulin resistance is a general term meaning that insulin does not exert its normal effects in insulin-sensitive target tissues, such as skeletal muscle, adipose tissue, liver, heart and pancreas, the major target tissues for insulin action in glucose metabolism. Insulin resistance, measured using the clamp technique, is associated with asymptomatic atherosclerosis (Laakso et al., 1991) and CAD (Bressler et al., 1996) in individuals without DM. Fasting insulin levels, a marker of insulin resistance, have also been associated with CV events in nondiabetic individuals, independent of other risk factors (Laakso, 2001, 1996). Insulin resistance can promote atherogenesis and plaque progression via multiple mechanisms, including changes in insulin signaling pathways (Bornfeldt and Tabas, 2011), and through their effects on CV risk factors. Impairment of insulin signaling at multiple points in the insulin signaling pathway in endothelial cells (Muniyappa et al., 2007; Potenza et al., 2009), vascular smooth muscle cells (Wang et al., 2004; Suzuki et al., 2001), and macrophages (Bornfeldt, 2014) promotes development and progression of atherosclerosis, as does the pro-inflammatory state induced in insulin resistance (Fig. 1). Insulin resistance alone or combined with hyperglycemia promotes adverse changes in CV risk factors, including pro-atherogenic dyslipidemia and blood pressure elevation (Ferrannini et al., 2007; Golden et al., 2002; Eckel et al., 2005), which contribute to the development, progression, and complexity of atherosclerosis.

Conclusions

T2DM is characterized by multiple genetic defects causing insulin resistance and progressive insulin deficiency. The evolving knowledge of the pathophysiology of diabetes is giving way to the development of various agents to address the spectrum of these defects. Treatment should be based on the pathophysiology of the disease and needs to consider factors such as expected hemoglobin A1c decrease, blood sugar control pre- and post-meal, patient tolerance, effect on weight and comorbidities, and cost of therapy. Clinicians must effectively use the available published guidelines as well as lifestyle intervention, DSME and regular monitoring to aggressively treat their patients with prediabetes and T2DM beginning at the onset of abnormal glycemia.

9.4 Hyperglycemia, Oxidative Stress, and Impaired Insulin Secretion

Hyperglycemia is the major feature of diabetes mellitus caused by either insulin insufficiency or insulin resistance. Although numerous causative factors have been implicated in the pathophysiology of diabetes mellitus, oxidative stress seems to play a critical role [14]. Pancreatic β cells are particularly vulnerable to increased oxidative stress. The insulin gene is expressed almost exclusively in pancreatic β cells, and metabolic regulation of insulin gene expression is essential for proper secretion of insulin by pancreatic β cells. Although glucose is the major physiological regulator of insulin gene expression, chronic hyperglycemia (glucotoxicity) and elevated lipid concentrations (lipotoxicity) result in worsening of β cell functions in patients with type 2 diabetes, partly due to inhibition of insulin gene expression [15]. Fatty acid levels are also significantly elevated in patients with diabetes mellitus compared to healthy individuals. Prolonged exposure of pancreatic β cells to elevated levels of fatty acids impairs β cell function, causing impaired insulin secretion. Kelpe et al. [16] demonstrated that elevated levels of palmitate affect insulin gene expression via transcription mechanisms and ceramide synthesis. Hyperglycemia has also been noted to inhibit the functionality of the insulin promoter region because hyperglycemia can induce loss of two critical proteins (pancreatic and duodenal homeobox factor-1 and macrophage-activating factor A) that play important roles in the activation of the insulin promoter region [17,18]. Hyperglycemia can further compromise the promoter region of the insulin gene by upregulating the transcription factor C/EBP (also called CCAAT-enhancer binding protein; CCAAT stands for cytidine–cytidine–adenosine–adenosine–thymidine), which functions to repress insulin promoter activity [19]. Additional deleterious effects of hyperglycemia include induction of endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress-induced insulin resistance [20]. Although each effect differs mechanistically, collectively they alter glucose homeostasis and lead to increasingly elevated physiological concentrations of glucose. Studies have shown an increased apoptotic rate in β islet cells cultured in varying concentrations of glucose [21].