Review on Diabetes Mellitus and Study the Combination Effect of Dapagliflozin, Sitagliptin and Metformin

Diabetes is a long-term metabolic condition and was first documented by an Egyptian and was founded a symptoms like weight reduction and polyuria. It was a Greek Physician Aertaeus who coined term Diabetes Mellitus, in which ‘Diabetes’ means ‘to pass through’ and ‘mellitus’ which relate the Latin term ‘honey.’(1). Over past years, various studied have been attempt to know about the spreadness of diseases, Moreover Previous studied have been done with multiple times through different blood sampling, making it impossible to calculate the diabetes prevalence.(2) According to recent 8 edition of international diabetes federation (IDF) Diabetes Atlas 2017 diabetes is rise across the world, and about 244.9 million people suffer from this disorder which further extend to 48%by 2045.(628.6)million.(3)The WHO observed in 2016 data that the increase in weight and obesity in women leads to  suffer from this metabolic syndrome.(4)Basically, on the basis of classification there are two type of diabetes i.e. Insulin dependent (type1) and Non-Insulin Dependent(type2),There is an evidence that regulation of blood glucose level reduces chances of diabetes and prevent the damage of eye, kidney and nerves. (5). Diabetes insipidus is an uncommon illness that causes frequent urination and thirst. One of the main causes of the polyuria polydipsia syndrome is diabetes insipidus, which is characterized by polydipsia of more than 3 L/d and a high hypotonic urine output mechanism. There are two basic kinds of diabetes insipidus: those with central or renal origin) as well as secondary polyuria (due to original polydipsia). Also referred to as hypothalamic or neurogenic diabetes insipidus. Central diabetes insipidus is a condition that due to insufficient synthesis and production of arginine vasopressin. (AVP) in the neurohypophyseal system of the hypothalamus in response to osmotic stimulation. The majority of cases are caused by illnesses that interfere with neurohypophysis. (6) Majorly, (T2DM) accounts for more than 90% of instances of diabetic mellitus. Still, Diabetes mellitus forms are frequently not differentiated in estimations at the population level; as a result, in this Review, all forms of diabetes are referred to as diabetes mellitus, unless otherwise noted. Despite the genetic, An individual's architecture may determine  reaction to modifications in the surroundings the primary motivators of the T2DM pandemic worldwide are the increases in obesity, a population that is sedentary, consumes foods high in calories, and ageing.(7)

Over the past three decades, diabetes mellitus has tripled in frequency globally, ranking as the ninth largest cause of death. Type 2 diabetes accounts for 90% of all occurrences of diabetes, which affects around one in eleven people worldwide. China and India are the main epicentres of the rapidly spreading worldwide T2DM epidemic, which is mostly an Asian problem. Mostly Genetic factors contributes to individual susceptibility to T2DM, an unhealthy diet and sedentary lifestyle are significant drivers of the current global epidemic; early developmental factors (such as intrauterine exposures) also influence susceptibility to T2DM later in life. Some cases of T2DM could be prevented with lifestyle adjustments, such as keeping a healthy body weight, eating a healthy diet and keep body fit by doing regular exercise and daily walk for at least 10,000 feet. Cardiovascular problems account for the majority of complications experienced by people with type 2 diabetes, and are the primary cause of morbidity and death in this patient population. An updated perspective on the global epidemiology of type 2 diabetes (T2DM), together with dietary, lifestyle, and other risk factors for T2DM and its consequences, are provided by this review.(8)

Insulin resistance and β-cell dysfunction are the two primary signs of diabetes mellitus (T2DM), which are caused by a disturbance in homeostasis. A vicious trio of β-cell failure (~80% of their β-cell activity) and insulin resistance in the muscles and liver is the main source of physiological issues. Although T2DM is often thought to be an insulin resistance and deficiency issue, recent studies on the disease's biology suggest that other significant components may also play a role in insulin shortage and associated functional impairment. The pancreatic islet is composed of β-cells (48–59%) that release insulin, α-cells (33–46%) that release glucagon, δ-cells that produce somatostatin, and F cells that release polypeptides in a similar proportion. Additionally, paracrine interactions take place in the order of β-cell to α-cells followed by delta cells and polypeptide cell. Although β-cell interactions are currently the focus, other pancreatic cell interactions are also very important and require further investigation to fully understand their involvement in glucose homeostasis. Furthermore, fat cells (accelerated lipolysis), the gastrointestinal tract (incretin deficiency/resistance), α-cells (hyperglucagonemia), the kidneys (increased glucose reabsorption), the brain (insulin resistance), and the intricate interactions that take place between these factors and T2DM associated genes all play a significant role in the development of glucose resistance in T2DM (9).

Mechanism involves in type 1 Diabetes mellitus

Type 1 diabetes is a chronic autoimmune disorder, characterized by T lymphocytes attacking insulin-producing beta cells. Previous clinical trials have found that continued Immune suppression temporarily reduces the Insulin production. Preclinical investigations indicated that a monoclonal antibody targeting CD3 may reverse Hyperglycaemia upon presentation induces tolerance a recurring sickness. Antibody treatment basically decrease the glycosylated haemoglobin level. Basically type 1 diabetes is insulin dependent diabetes. (10)

Autoimmune Destruction

The main mechanism involve in T1DM is that immune system of body automatically target   or deplete the beta cells. This destruction is mediated primarily by autoreactive T cells, which are part of the normal immune repertoire. And further these T cells target the beta cells, leading to their subsequent loss or inability to produce insulin. (11)

Genetics

Type 1 diabetes usually affects people without a family history of the condition. Of patients, only 10 to 15 percent had a first- or second-degree family with the disease. About 50% of monozygotic twins, 5% of siblings, and 6% of children develop type 1 diabetes, compared to the 0.4% prevalence in the general population. Accordingly, family members of sufferers are far more likely to get type 1 diabetes throughout their lives. Over 50% of people with type 1 diabetes are genetically at risk, according to meta-analyses and genome-wide association studies. The bulk of the genes that predispose to type 1 diabetes are located on chromosome 6 in the Major Histocompatibility Complex (MHC) area, sometimes referred to as HLA (Human Leucocyte Antigen). Between 40 and 50 percent of the hereditary risk for type 1 diabetes is occur by polymorphic alleles in HLA complex. (12)

Consequences of beta cell loss

Due to the beta cell destruction, the regulation of blood glucose level impaired. This lead to hyperglycaemia which is an indication of diabetes. This affect the alfa cell also which secrete glucagon and make complication in glucose homeostasis and contributing the metabolic dysregulation seen T1DM. (13)

A new era of immunotherapies for people with type 1 diabetes

In contrast to previous widely immunosuppressive regimens, more sophisticated therapies have been developed in the last 20 years to treat autoimmune and inflammatory diseases. Examples of these therapies include rituximab and anti-tumor necrosis factor [TNF] therapy for rheumatoid arthritis, which have more limited side effects. Applying this idea to T1D, a paradigm change in the field's development of T1D immunotherapy toward the targeting of islet-specific immune pathways involved in tolerance has resulted in the creation of treatments that have the potential to prevent or reverse the disease while avoiding the toxicities of earlier immunosuppressive methods. As a result, The field has been testing these medications in high-risk and new-onset situations for the past ten years in order to determine the biomarker of C-peptide preservation. (14)

Targeting T cell

T1D patients are presently undergoing testing for more targeted and less harmful T cell-directed treatments, which appear promising. First created in the mid-1980s as a modified version of OKT3, the first authorized monoclonal antibody used to treat acute kidney allograft rejection, targeted CD3 blockage started with an engineered, humanized antibody. However, the cytokine storm that was brought on by the drug's early mAb-activating qualities and subsequent immunogenicity resulted in serious adverse effects. In order to minimize T cell activation and immunogenicity, a mutant human Fc receptor was used in the development of teplizumab (hOKT3g [Ala-Ala]), a modified humanized variant of the antibody. Teplizumab was demonstrated to overcome kidney transplant rejection in 1995 small pilot research in a manner comparable to the parent OKT3 mAb without the previously mentioned side effects. A brief course of anti-CD3 mAb was also discovered to be able to produce a long-term remission of autoimmune diabetes in NOD mice in preclinical research conducted in the 1990s . This discovery laid the groundwork for the translation of anti-CD3 mAb into T1D. After just one 2-week course of treatment, individuals with newly diagnosed T1D demonstrated clinical safety and effectiveness of teplizumab, almost 7 years after the drug's original development. One possible explanation for the medication treatment's limitations (most patients' condition did not improve) might be a low initial beta cell mass. A phase 3 trial is now being conducted to see if teplizumab may change the course of the disease considerably in the new-onset situation. Patients treated with otelixizumab, a related monoclonal antibody, showed results in early phase 2 studies that showed intact b cell function ; nevertheless, because of the mAb's immunosuppressive and cytokine-activating characteristics, there was an increased risk of EBV reactivation. In the DEFEND-1 and DEFEND-2 phase 3 trials , follow-up studies utilizing lower dosages were unable to achieve main objectives of retained C peptide, and no registered clinical trials are presently being conducted. Minimal dosage While less selective than anti-CD3 medicines like teplizumab, ATG is another T cell strategy being tested for T1D prevention and reversal. Since ATG is produced by immunizing rabbits with human thymocytes, it is a pure rabbit sera with cytotoxic IgG antibodies directed against human T cells. As a result, it does not target a specific epitope, and repeated exposures may raise the risk of serum sickness.(15)

Human K+ channel Kv1.3 regulates membrane potential and Ca2+ signaling in T cells; its expression is four to five times higher in memory and activated CD4+ and CD8+ T cells, especially Tem cells. Since Kv1.3 becomes the main functional K+ channel and is upregulated to 1500–2000 channels per cell in activated stem cells (CD45RA−/CCR7), it has been recognized as a potential signature biomarker in these cells. Kv1.3 is highly expressed in the parenchyma of demyelinated MS lesions, perivenular infiltrates, and post-mortem MS brain inflammatory infiltrates. Kv1.3+ cells are composed of CCR7− CD4+ and CD8+ Tem cells, confirming earlier studies that demonstrated activated memory T cells constitute an essential part of MS lesions in the brain. In both RA and T1D, illness-associated autoreactive T cells mostly have a high Kv1.3 expression profile. It has been demonstrated that autoreactive Tem cells from RA and T1D patients preferentially block the synthesis and proliferation of cytokines by small-molecule Kv1.3 inhibitors in vitro. Furthermore, in rat models of RA and T1D, these inhibitors were shown to enhance autoimmunity without resulting in systemic harm.(16)

Kv1.3Channel inhibitor-

Membrane potential, like T cells, is controlled by the Kv1.3 k+ channel in humans, and its expression is fourfold to fivefold higher in activated and memory CD4+ and CD8+ T cells, particularly Tem cells. In activated Tem cells (CD45RA−/CCR7), Kv1.3 increases to 1500-2000 channels per cell and becomes the primary functional K+ channel, making it a potential biomarker. Kv1.3 is highly expressed in postmortem multiple sclerosis (MS) brain inflammatory infiltrates, as well as in perivenular infiltrates and demyelinated MS lesion parenchyma.Kv1.3+ cells are CCR7− CD4+ and CD8+ Tem cells, indicating the presence of activated memory T cells in MS brain lesions, as previously discovered. Similarly, in both RA and T1D, disease-associated autoreactive T cells are mainly Tem, with high Kv1.3 expression. Small-molecule Kv1.3 inhibitors were discovered to specifically decrease cytokine generation and proliferation of autoreactive Tem cell from RA and T1D patient in vitro and improved immunity. There were no evidence of systemic toxicity in rat models of RA and T1D.(17)

Type 2 Diabetes mellitus-

Insulin resistance, a disorder in which cells do not use insulin as it should, can occasionally be paired with a complete lack of insulin to cause type 2 diabetes mellitus. Other names for it include adult-onset diabetes and non-insulin-dependent diabetes mellitus. Approx  90% cases of diabetes are type 2 diabetes caused by -

• Abnormality in gluco-receptor of beta cell so they respond at higher level of glucose.
• Reduced sensitivity of peripheral tissue to insulin receptor.
• Excess hyperglycaemic hormone or over excess production of glucagon.

Factor affecting type 2 diabetes mellitus-

Age

The terms "adult onset" and "maturity-onset" have been used for many years to describe type 2 diabetes, indicating that the condition is more common as people age. Of the total population 65 years of age and older, 18.4% have diabetes. One at 75 years of age or older, several polls indicate a plateauing or mild deterioration.6. Noteworthy, a significant cut-off point for determining the prevalence of diabetes has historically been set at 45 years of age. However, type 2 diabetes has shockingly increased by 70% in younger individuals (ages 30-39) over the past eight years. One Rates increased by a sharp 40% for the 40–49 age range. Current lifestyle trends are responsible for these shocking numbers, which lead to increase excess.

GESTATIONAL DIABETES MELLITUS (GDM)

Gestational diabetes is defined as any degree of intolerance of glucose that occur or is first recognized during pregnancy. GDM affects around 4% of all pregnancies in the United States, but the range varies greatly (1-14%) according on the racial or ethnic groups analysed, as well as the frequency of obesity. Increased screening and detection rates, as well as the trend of older women having children, may contribute to the development of GDM to diabetes. In the Nurses’ Health Study, pregravid factors of GDM were investigated. The following factors were identified to indicate a woman's risk for GDM: cigarette smoking, weight increase in early adulthood, advanced maternal age, non-white ethnicity, higher BMI, and family history of diabetes. There are differences in the rates at which GDM progresses to diabetes; the risk of type 2 diabetes increases from 5% in the first three to six months after giving birth to 47% at the 5-year mark.15 Review of other research showed that women with previous GDM had a 40% chance of developing diabetes at age of 15.According to high-risk ethnic groups, 50% of women develop diabetes within five years, indicating that ethnicity has a significant impact on the development of diabetes following a GDM pregnancy. Of fact, these ethnic groups' stated rates of obesity and physical inactivity also serve as confounding variables that are reported in all the women that affect the progression in diabetes. (18)

(IFG) AND (IGT)

IFG and IGT act as median in normalglycemia and diabetes. IFG criteria include those with fasting blood glucose levels between 110 and 125 mg/dl. An oral glucose tolerance test value of $140 mg/dl but 200 mg/dl after two hours is used to calculate IGT. IGT patients have normal glycemic levels for the majority of their life; glucose tolerance testing is the only way to identify the metabolic abnormality. Particularly among non-white racial and cultural groups, IGT suggests an elevated risk of type 2 diabetes development, ranging from 2.3 to 11% annually. Women are more likely to be in each minority group. Diabetes etiology is directly impacted by insulin resistance and the ensuing IGT. According to data from six prospective studies involving a variety of groups, increased fasting and 2-hour post-challenge glucose levels were the most reliable indicators of the transition from IGT to type 2 diabetes. The identification of IGT is very important since it is a substantial risk factor for type 2 diabetes and indicates chronic insulin resistance.(19)

Lifestyle factor correlation

Type 2 diabetes is largely caused by lifestyle factors, such as smoking, alcohol use, physical inactivity, and sedentary behavior. The most important risk factor for type 2 diabetes has been shown to be obesity, which may influence insulin resistance and the course of the illness. The World Health Organization (WHO, 2011) estimates that around 90% of people with diabetes develop type 2 diabetes, which is mostly brought on by obesity. Moreover, obesity has a strong genetic component. Many overweight and obese people suffer from obstructive sleep apnea (OSA), a treatable sleep disorder that has been found to be a distinct, modifiable risk factor for insulin resistance and glucose intolerance. People who have healthy lifestyles that include eating a balanced diet, exercising frequently, and keeping their weight in check have a decreased incidence of hyperglycemia, according to studies.In particular, the risk of diabetes might increase by up to 89% when these low-risk behaviors are absent. Numerous studies have shown that OSA is much more prevalent in T2DM patients (36%–60%) than in the general population. Diet is also thought to be a significant determinant for type 2 diabetes.

Gut metagenome correlation

The gut metagenome has been implicated in the development of type 2 diabetes in a few recent investigations. Bacterial chemotaxis, flagellar assembly, butyrate biosynthesis, and cofactor and vitamin metabolism are all reduced in type 2 diabetic patients, while membrane transport of sugars, methane metabolism, branched-chain amino acid (BCAA) transport, xenobiotic degradation and metabolism, and sulphate reduction are all increased. Seven of the T2DM-enriched KEGG orthologues' indicators were connected to oxidative stress resistance, per a research. Among these indications were glutathione reductase (NADPH) (K00383), nitric oxide reductase (K02448), catalase (K03781), peroxiredoxin (K03386), cytochrome c peroxidase (K00428), putative iron-dependent peroxidase (K07223), Mn-containing catalase (K07217), and k00383 measures. The gut microbiota of individuals with type 2 diabetes shows a reduction in butyrate bA, flagellar assembly, and bacterial chemotaxis. By comparing the T2DM score with the proportion of T2DM patients, the gut microbiota-based T2D classifier approach correctly categorizes individuals with type 2 diabetes.For example, "functional dysbiosis" rather than a specific microbial species may be the cause of dysbiosis in T2DM patients, while bacteria that produce butyrate may provide protection against many illnesses.Gut metagenomic indicators show more specificity in distinguishing between T2DM patients and controls based on human genome variation, indicating that they might be a useful supplementary technique to monitor gut health for determining the risk of the illness. (20)

Stress and lack of sleep

Compared to males, women are more negatively impacted by discrimination and PTSD in terms of their sleep quality. A study of epidemiological research by sex revealed that women of all ages were 40% more likely to have insomnia. Loss of sleep, short sleep duration, and poor sleep quality were then linked to obesity and, to a greater extent, to impaired glucose metabolism brought on by insulin resistance. Short sleep duration (less than five hours) and trouble falling or staying asleep were linked to increased risk for diabetes in a meta-analysis. After sex-based stratification, however, similar impact estimates were reported in both sexes. In a smaller prospective research with sex differences as the main outcome, sleep deprivation increased food and fat consumption, but men were more likely to gain weight due to higher daily calorie intake, particularly at night. According to the findings of a meta-analysis of observational studies that included sex-specific subgroup analysis, shift employment was linked to an increased risk of diabetes in males. There are often conflicting findings about the effects of shift work, work stress, and coping that relate to sex and gender differences.(21)

Foetal Programming/Epigenetics in Animals

Since there are few studies on the impact of epigenetics on the risk of diabetes in humans, we mostly depend on research conducted on rodents.There is proof that maternal undernutrition or hyperglycemia, in an epigenetic way, causes sex-specific intragenerational transfer of glucose tolerance and fat distribution from one generation to the next. In mice, obesity exclusively progresses down the maternal line, but IGT was passed down through both parental lineages. Birth weight loss only manifests when it is passed down from the F1 to the F2 generation via the paternal line. However, in a different investigation, it was discovered that defective glucose-tolerant paternal lines significantly increased the birth weight of F2.

Offspring of mice fed a high-fat diet (HFD) showed sex variations in glucose metabolism. Compared to female mice, male progeny in the HFD group had reduced insulin content, islet area, and insulin production, as well as higher oxidative stress. Compared to male offspring, female mice whose moms were fed a regulated diet had reduced levels of estrogen. One possible explanation for the sex difference is that male beta cells experience greater levels of oxidative stress, which is linked to lower amounts of estradiol and may result in a loss of beta cell protection. IGT was previously shown in both male and female offspring of obese mice during gestation and lactation in overfed animals. Male offspring of fat moms had similar abnormalities, including reduced pancreatic insulin concentration. Additionally, among the category of fat descendants regardless of sex, insulin levels were greater than in the control animal group.(22)

Pathophysiology of hyperglycaemia in T2DM

Insulin release from the pancreatic β-cells typically enhances the absorption of glucose by skeletal muscle and adipose tissue while decreasing the liver's production of glucose. Hyperglycaemia, or an excess of glucose in the blood, arises when β-cell failure in the pancreas and/or insulin resistance in the liver, skeletal muscle, or adipose tissue take place. The several elements mentioned at the top have an impact on insulin action and secretion in type 2 diabetes mellitus. Elevated free fatty acid and proinflamatory cytokines contribute to insulin resistance, while excessive glucagon secretion further elevates blood glucose level. Chronic hyperglycaemia can induce oxidative stress, resulting in complication such as neuropathy and cardiovascular disease .Effective management is crucial to mitigate these risk. (23)

Mechanisms leading to β-Cell Dysfunction-;

Hyperglycaemia and hyperlipidaemia are frequently present in an over nutrition condition, which favours IR and chronic inflammation, much like in obesity. Because of differences in their inherited sensitivity, β-cells are vulnerable to toxic stimuli such inflammation, inflammatory stress, ER stress, metabolic/oxidative stress, and amyloid stress, which can result in a loss of islet integrity. β-cells are harmed by the metabolic and oxidative stress brought on by lipotoxicity, glucotoxicity, and glucolipotoxicity in obesity. There are several ways that stress caused by high saturated FFA levels might activate the UPR pathway, including by directly disrupting ER homeostasis, activating IP3 receptors, or inhibiting the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), which is responsible for ER Ca2+ mobilization. Additionally, chronically high glucose levels speed up the β-cells' synthesis of proinsulin and islet amyloid polypeptides (IAAP), which leads to the accumulation of misfolded insulin and IAAP and increases the creation of reactive oxygen species (ROS) through oxidative protein folding. In addition to promoting proapoptotic signals, proinsulin mRNA degradation, and the generation of interleukin (IL)-1 β, which draws macrophages and heightens local islet inflammation, these activities alter the mobilization of normal ER Ca2+. As mentioned before, insulin production needs to be strictly regulated in order to precisely meet metabolic demand. Enough islet integrity must be maintained for β-cells to react to metabolic demands. In pathological conditions, the aforementioned mechanism may ultimately lead to disruption of the integrity and organization of the islets, hinder the best possible cell-to-cell communication within the pancreatic islets, insufficiently regulate the release of insulin and glucagon, and worsen hyperglycemia. Insulin secretory dysfunction is the primary cause of β-cell failure and the root cause of type 2 diabetes. It can be brought on by abnormalities in the secretion process or by flaws in the synthesis of insulin or any of its precursors. For instance, the downstream signaling cascade would be impacted by reduced expression of the GLUT2 glucose transporter, and proinsulin folding failure is another result that is commonly linked to diabetes and insufficient insulin production.(24)

Hormonal regulation-

Treatment and prevention of type 2 Diabetes mellitus

Management of type 2 diabetes mellitus involves a combination of lifestyle changes and medication. A heart-healthy, low-carb diet, exercise, weight loss, and the use of oral or injectable anti-diabetic medications are all part of the therapy of hyperglycemia in type 2 diabetes. Anti-hyperglycaemic therapies include substances that facilitate insulin production, such as meglitinides and sulfonylureas, or that improve insulin availability (either by administering insulin injections, or indirectly through the incretin pathway, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors), enhance insulin sensitivity. Biguanide, thiazolidinediones, or sodium-glucose cotransporter-2 inhibitors that make urine more excretory of glucose. There are agents that operate through many mechanisms. It might be difficult to navigate this lengthy list of anti-hyperglycemic medications for doctors. Providers treating patients with type 2 diabetes must be well-versed on the particular hazards and advantages of each drug class and its constituent agents as treatment should be tailored to each patient's specific circumstances.(25)

Overcome insulin resistance

(a) Biguanides