**1. Diabetes: the "silent killer"**

Diabetes mellitus (DM) is defined as "a heterogeneous syndrome characterized by a complex disorder in regulating the body's energy metabolism, which also affects the use of carbohydrates, lipids and proteins" [1]. Several processes are involved in the evolution of diabetes pathology ranging from autoimmune pancreatic β cells destruction that induces insulin deficiency, up to anomalies, which causes insulin resistance. Increased blood glucose levels (≥126 mg/dL), blood glucose at 2 h after 75 g oral glucose (≥200 mg/dL), HbA1c (≥6.5%), or all of them characterize diabetes mellitus simultaneously. The American Diabetes Association (ADA) has classified diabetes mellitus into several types: (i) type 1 DM (T1D)—characterized by the destruction of pancreatic β cells; (ii) type 2 DM (T2D)—characterized by a progressive deficiency of insulin secretion on a background of pre-existing insulin resistance; (iii) gestational DM—diabetes diagnosed during pregnancy; and (iv) other specific types of diabetes due to other causes such as genetic defects of β pancreatic cells, genetic defects in the action of insulin, diseases of exocrine pancreas, endocrinopathies, diabetes induced by drugs or chemicals, etc. Type 1 diabetes (T1D) also known as juvenile diabetes or insulin-dependent diabetes mellitus is a very common autoimmune disorder in children and adolescents, and it is caused by the cellular-mediated autoimmune destruction of pancreatic β-cells, leading to an absolute insulin deficiency, which interferes with glucose metabolism [2]. T1D has two variants: (i) type I A is due to the destruction of the pancreatic cells under the influence of immune factors, in which case autoantibodies to islet cells can be detected in serum and (ii) type I B in which the pancreatic β-cell lysis occurs in the absence of an obvious anti-pancreatic mechanism [3]. Patients with this type of diabetes are usually young (under 30 years), have normal weight and require continuous insulin administration for survival. T1D symptoms are usually present with the onset of hyperglycaemia and include polyphagia, polydipsia, polyuria, weight loss, paraesthesia, recurrent infections and ketoacidosis tendency. The T1D prevalence of 1:300 is increasing worldwide, and it represents 5–10% of all diabetes mellitus cases [4]. The main cause of T1D is genetic predisposition with the human leucocyte antigen (HLA) DR3-DQ2 and DR4-DQ8 haplotypes as the most prevalent variants involved, which are common for other autoimmune diseases such as celiac disease [5]. Besides genetic predisposition, other factors such as infections, birth delivery mode, diet and the use of antibiotics have all been linked to T1D development [6], but the mechanisms linking them to T1D development are not clear.

visceral or abdominal type of obesity (visceral fat tissue is more metabolically active than the subcutaneous adipose tissue), producing pro-inflammatory adipokines and peripheral insulin resistance. According to the ADA guidelines of 2016: "Standards of medical care in diabetes" (Diabetes Care), the criteria for the diagnosis of T2D refer to: (i) Glucose concentration in venous blood (fasting plasma glucose) ≥126 mg/dL (7.0 mmol/L) in at least two consecutive determinations, measured after at least 8 h of fasting; (ii) Glucose concentration in venous blood 2 h after oral glucose tolerance test—OGTT—(ingestion of 75 g of anhydrous glucose dissolved in water) ≥200 mg/dL (11.1 mmol/L); (iii) HbA1C ≥48 mmol/mol determined in the medical laboratory by the National Glycohemoglobin Standardization Program (NGSP) and standardized by DCCT (Diabetes Control and Complications Trial); and (iv) Glucose concentration in venous blood ≥200 mg/dL (11.1 mmol/L) randomly determined in hyperglycaemic individuals. Some potential risk factors for T2D are family history and race. Specifically, Hispanic, Asian American, or Indian Americans are at greater risk to develop T2D. Age is another risk factor worth considering, as individuals who are 40–45 years old or older have a greater risk for developing the condition. Diabetic patients have an increased incidence of cardiovascular disease, atherosclerosis, peripheral arteriopathy and cerebrovascular disease. Long-term complications of diabetes include retinopathy with possible loss of vision, nephropathy followed in time by renal insufficiency, peripheral neuropathy with risk of leg ulceration and amputation. Neuropathy autonomously induces gastrointestinal, genitourinary, cardiovascular and sexual dysfunction. Like most other conditions, the earlier that diabetes is detected, the more successfully it can be managed. There is no cure for type 2 diabetes, but it can be very well managed if identified early. The latest data released by a group of WHO experts provide an alarming prognosis of the diabetes epidemic. It is estimated that by 2025, there will be 324 million people with diabetes. Thus, the prevalence will increase from 2.8% (2000) to 4.3% (2025). The T2D epidemic is considered one of the worst in the history of humankind. What is alarming, however, is that at the time of T2D diagnosis, a large percentage of people already have chronic complications and/or morbid associations. The WHO predictions for 2030 place T2D as the seventh cause of death worldwide. Epidemiological data revealed an increased prevalence for both obesity and T2D in developed countries, suggesting the role of diet and lifestyle in the pathogenesis of these two diseases [1]. Recently, it has been shown that overeating saturated fats and refined sugars can lead to dyslipidemia and insulin resistance. Thus, T2D prevalence is directly proportional to the energy intake of saturated fatty acids [8]. Currently, type 2 diabetes is most commonly encountered in most cases associated with overweight or obesity in adults. WHO classifies obesity grades by

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the formula: Body Mass Index (BMI) = weight/height2

; (ii) Grade I obesity—BMI 30–34.9 kg/m2

(iv) Grade III obesity—BMI > 40 kg/m2

m<sup>2</sup>

in: (i) Overweight—BMI 25–29.9 kg/

; and

; (iii) Grade II obesity—BMI 35–39.9 kg/m2

. In T2D, the most common type of obesity is the cen-

tral or abdominal type [9]. An increased prevalence of T2D in the predominantly abdominal distribution of adipose tissue was reported independent of the degree of obesity [10]. On the other hand, there are studies that show that obesity is not sufficient or mandatory for the appearance of T2D. In support of this hypothesis, there are several arguments: the presence of T2D in a normal weight phenotype, the existence of populations with high prevalence of obesity, but the low prevalence of T2D, the predominance of obesity in females, in contrast to that of T2D that does not differ between genders and finally data according to which in most

DM type 2 (T2D) comprises a heterogeneous group of conditions characterized by varying degrees of insulin resistance or inappropriate insulin secretion and elevated plasma glucose (hyperglycaemia). Hyperglycaemia of this type of diabetes is due to genetic or metabolic defects of insulin synthesis and/or secretion, which once identified have become particularly important in discovering new effective therapeutic means. Pre-diabetes stages (IFG and IGT) typically precede T2D [7]. T2D appears at the age of 40 or above and is not associated with autoimmune aetiology but with metabolic syndrome involving hypertension, atherosclerotic cardiovascular disease, low high density lipoprotein cholesterol (HDLc), high circulating level of low density lipoprotein cholesterol (LDLc), decreased fibrinolysis, increased plasma lipopolysaccharide (LPS) due to alteration of mucosal permeability, obesity and especially visceral or abdominal type of obesity (visceral fat tissue is more metabolically active than the subcutaneous adipose tissue), producing pro-inflammatory adipokines and peripheral insulin resistance. According to the ADA guidelines of 2016: "Standards of medical care in diabetes" (Diabetes Care), the criteria for the diagnosis of T2D refer to: (i) Glucose concentration in venous blood (fasting plasma glucose) ≥126 mg/dL (7.0 mmol/L) in at least two consecutive determinations, measured after at least 8 h of fasting; (ii) Glucose concentration in venous blood 2 h after oral glucose tolerance test—OGTT—(ingestion of 75 g of anhydrous glucose dissolved in water) ≥200 mg/dL (11.1 mmol/L); (iii) HbA1C ≥48 mmol/mol determined in the medical laboratory by the National Glycohemoglobin Standardization Program (NGSP) and standardized by DCCT (Diabetes Control and Complications Trial); and (iv) Glucose concentration in venous blood ≥200 mg/dL (11.1 mmol/L) randomly determined in hyperglycaemic individuals. Some potential risk factors for T2D are family history and race. Specifically, Hispanic, Asian American, or Indian Americans are at greater risk to develop T2D. Age is another risk factor worth considering, as individuals who are 40–45 years old or older have a greater risk for developing the condition. Diabetic patients have an increased incidence of cardiovascular disease, atherosclerosis, peripheral arteriopathy and cerebrovascular disease. Long-term complications of diabetes include retinopathy with possible loss of vision, nephropathy followed in time by renal insufficiency, peripheral neuropathy with risk of leg ulceration and amputation. Neuropathy autonomously induces gastrointestinal, genitourinary, cardiovascular and sexual dysfunction. Like most other conditions, the earlier that diabetes is detected, the more successfully it can be managed. There is no cure for type 2 diabetes, but it can be very well managed if identified early. The latest data released by a group of WHO experts provide an alarming prognosis of the diabetes epidemic. It is estimated that by 2025, there will be 324 million people with diabetes. Thus, the prevalence will increase from 2.8% (2000) to 4.3% (2025). The T2D epidemic is considered one of the worst in the history of humankind. What is alarming, however, is that at the time of T2D diagnosis, a large percentage of people already have chronic complications and/or morbid associations. The WHO predictions for 2030 place T2D as the seventh cause of death worldwide. Epidemiological data revealed an increased prevalence for both obesity and T2D in developed countries, suggesting the role of diet and lifestyle in the pathogenesis of these two diseases [1]. Recently, it has been shown that overeating saturated fats and refined sugars can lead to dyslipidemia and insulin resistance. Thus, T2D prevalence is directly proportional to the energy intake of saturated fatty acids [8]. Currently, type 2 diabetes is most commonly encountered in most cases associated with overweight or obesity in adults. WHO classifies obesity grades by the formula: Body Mass Index (BMI) = weight/height2 in: (i) Overweight—BMI 25–29.9 kg/ m<sup>2</sup> ; (ii) Grade I obesity—BMI 30–34.9 kg/m2 ; (iii) Grade II obesity—BMI 35–39.9 kg/m2 ; and (iv) Grade III obesity—BMI > 40 kg/m2 . In T2D, the most common type of obesity is the central or abdominal type [9]. An increased prevalence of T2D in the predominantly abdominal distribution of adipose tissue was reported independent of the degree of obesity [10]. On the other hand, there are studies that show that obesity is not sufficient or mandatory for the appearance of T2D. In support of this hypothesis, there are several arguments: the presence of T2D in a normal weight phenotype, the existence of populations with high prevalence of obesity, but the low prevalence of T2D, the predominance of obesity in females, in contrast to that of T2D that does not differ between genders and finally data according to which in most

**1. Diabetes: the "silent killer"**

70 Pathophysiology - Altered Physiological States

development are not clear.

Diabetes mellitus (DM) is defined as "a heterogeneous syndrome characterized by a complex disorder in regulating the body's energy metabolism, which also affects the use of carbohydrates, lipids and proteins" [1]. Several processes are involved in the evolution of diabetes pathology ranging from autoimmune pancreatic β cells destruction that induces insulin deficiency, up to anomalies, which causes insulin resistance. Increased blood glucose levels (≥126 mg/dL), blood glucose at 2 h after 75 g oral glucose (≥200 mg/dL), HbA1c (≥6.5%), or all of them characterize diabetes mellitus simultaneously. The American Diabetes Association (ADA) has classified diabetes mellitus into several types: (i) type 1 DM (T1D)—characterized by the destruction of pancreatic β cells; (ii) type 2 DM (T2D)—characterized by a progressive deficiency of insulin secretion on a background of pre-existing insulin resistance; (iii) gestational DM—diabetes diagnosed during pregnancy; and (iv) other specific types of diabetes due to other causes such as genetic defects of β pancreatic cells, genetic defects in the action of insulin, diseases of exocrine pancreas, endocrinopathies, diabetes induced by drugs or chemicals, etc. Type 1 diabetes (T1D) also known as juvenile diabetes or insulin-dependent diabetes mellitus is a very common autoimmune disorder in children and adolescents, and it is caused by the cellular-mediated autoimmune destruction of pancreatic β-cells, leading to an absolute insulin deficiency, which interferes with glucose metabolism [2]. T1D has two variants: (i) type I A is due to the destruction of the pancreatic cells under the influence of immune factors, in which case autoantibodies to islet cells can be detected in serum and (ii) type I B in which the pancreatic β-cell lysis occurs in the absence of an obvious anti-pancreatic mechanism [3]. Patients with this type of diabetes are usually young (under 30 years), have normal weight and require continuous insulin administration for survival. T1D symptoms are usually present with the onset of hyperglycaemia and include polyphagia, polydipsia, polyuria, weight loss, paraesthesia, recurrent infections and ketoacidosis tendency. The T1D prevalence of 1:300 is increasing worldwide, and it represents 5–10% of all diabetes mellitus cases [4]. The main cause of T1D is genetic predisposition with the human leucocyte antigen (HLA) DR3-DQ2 and DR4-DQ8 haplotypes as the most prevalent variants involved, which are common for other autoimmune diseases such as celiac disease [5]. Besides genetic predisposition, other factors such as infections, birth delivery mode, diet and the use of antibiotics have all been linked to T1D development [6], but the mechanisms linking them to T1D

DM type 2 (T2D) comprises a heterogeneous group of conditions characterized by varying degrees of insulin resistance or inappropriate insulin secretion and elevated plasma glucose (hyperglycaemia). Hyperglycaemia of this type of diabetes is due to genetic or metabolic defects of insulin synthesis and/or secretion, which once identified have become particularly important in discovering new effective therapeutic means. Pre-diabetes stages (IFG and IGT) typically precede T2D [7]. T2D appears at the age of 40 or above and is not associated with autoimmune aetiology but with metabolic syndrome involving hypertension, atherosclerotic cardiovascular disease, low high density lipoprotein cholesterol (HDLc), high circulating level of low density lipoprotein cholesterol (LDLc), decreased fibrinolysis, increased plasma lipopolysaccharide (LPS) due to alteration of mucosal permeability, obesity and especially populations studied most obese individuals do not have T2D [1]. Cross-sectional studies have failed to determine a causal relationship between T2D and obesity or a common factor triggering both diseases, but prospective and longitudinal studies have provided some evidence of the direct role of obesity in T2D pathogenesis. Prospective studies on the populations of Japan, Sweden and the Pima Indians show that the central distribution of body adiposity is a major risk factor for the emergence of T2D, regardless of the degree of obesity [11]. However, these studies only suggest that insulin synthesis or deficiency obesity and defects predispose to T2D but offer little data on the duration of these anomalies or their interaction [1]. There is increasing evidence that adipose tissue has a limited capacity to store the energy surplus [12] and that overstressed adipocytes suffer a process of apoptosis or necrosis, precipitating an inflammatory response which contribute to the development of insulin resistance [13].

Indonesia, Thailand and Malawi have a diet with a low level of animal protein and fat and a high content of plant polysaccharides and fibre, which translate into a microbiota rich in *Prevotella*. Conversely, children from Japan, the United States, Italy and China have a Western diet rich in fat, animal protein and low in fibre and thus have a microbiota dominated by *Bacteroides* [17]. However, the enterotype hypothesis was recently challenged by Knights et al. who showed that

However, the highest microbial level (around 1012 cells) resides in the highly anaerobic environment of the colon. Since most of these microbes are not cultivatable, the advent of culture-independent sequencing has provided a valuable insight into the composition of the microbiota in health and disease conditions. Despite the large volume of data generated by sequencing technologies, our understanding of the functional properties of these microorganisms comes from germfree animals. Thus, animals, which were born and reared under sterile conditions, have provided strong evidence regarding the role of microbiota in shaping immunity, host metabolism and even social development. Unlike animals reared under specific pathogen-free (SPF) conditions, germfree animals were shown to have a defective development of the immune system with impaired development of the gut-associated lymphoid tissue, with fewer and smaller Peyer's patches [21].

The microbiota modulates the immune response of the host even before birth as suggested by the fact that the intrauterine environment is not completely sterile. Indeed, there is evidence that the placenta harbours a low-abundance commensal microbiota similar to the oral microbiota [22]. Thus, the foetus is exposed to antigens against which it has to develop immunological tolerance. Following birth, diet represents the crucial factor guiding microbiota composition as well as immunity. Dietary antigens correlated with T1D are modulated by feeding regimens (breast milk vs infant formula) and the introduction of solid foods (particularly of wheat). While infant formula has been historically associated with T1D, breast milk has beneficial immunomodulatory effects in the neonatal gut. Within this line of thought, studies in mice showed that sIgA transferred passively in breast milk promotes gut homeo-

Studies in Finnish and American children revealed that fat and protein intake from milk products promote a risk of advanced β-cell autoimmunity and consequently progression to T1D [24]. Patients with T1D and latent autoimmune diabetes of adults were shown to have elevated titres of anti-β-casein antibodies. Several bovine β-casein variants have a Pro-Gly-Pro-Ile-Pro motif in their sequence, which is also present in the glucose transporter GLUT2. Hence, a plausible explanation for pancreatic damage is a cross reactivity of the immune

T1D is similar in terms of its genetic HLA-associated risk with celiac disease and T1D children have an altered T-cell reactivity against wheat antigens in the gut [25]. Consequently, diets

microbial cells within the stomach

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The Intricate Relationship between Diabetes, Diet and the Gut Microbiota

microbial cells.

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enterotypes can vary widely and continuously over time within an individual [20].

into the duodenum and jejunum, whereas the distal ileum harbours around 108

**3. The immunity-diet-microbiota interplay in type 1 diabetes**

stasis and prevents bacterial translocation [23].

system initially targeted against the dietary antigen in milk.

The gastrointestinal (GI) tract of a healthy host is home to 102

The specificity of obesity in T2D is also the infiltration of adipose tissue with monocytes and activated macrophages leading to the synthesis of pro-inflammatory cytokines (IL-6 and TNF-α). Because of changes induced in the adipose tissue (lipolysis and lipids products), hepatic lipid synthesis (especially of very low-density lipoproteins-VLDL and triglycerides) occurs. Due to the changes in lipid metabolism, T2D is also characterized by dyslipidemia (elevated triglycerides, LDL-C levels and low HDLc) [14].
