Introduction
Endocrinology is that branch of medicine that focuses on the study of the endocrine system in the human body. It comprises of glands that have the ability to secrete hormones. These hormones are chemical agents that affect the actions/reactions of different organ systems in the body for its normal functioning. The most common disorder in hormones is glucose homeostasis disorder and in this category diabetes is well known. The latter is a group of metabolic diseases characterized by hyperglycemia that results from defects in insulin secretion, insulin action, or both. (1) Those patients who have diabetes undoubtedly have a higher risk of acquiring many of the life threatening health issues that comes with more medical care expenditure, poor/moderate quality of life and higher mortality rate. (2) The rapid change in diabetes prevalence in many countries and regions has been increased by rapid urbanization and major changes in one’s sedentary lifestyle. (3)
Global burden of diabetes
The global prevalence of diabetes and impaired glucose tolerance has been multiplying over the past decennium. (4) Diabetes is one of the major leading causes of morbidity and mortality in the world. This up-growing diabetes epidemic endeavors a major challenge to public health. (5) In a recent study it was estimated that in 2017 there were 451 million (age 18–99 years) people with diabetes worldwide. These figures are presumably expected to rise in number to 693 million by 2045. Furthermore it was also assumed that almost half of all people (49.7%) living with diabetes are still not diagnosed. According to WHO approximately 5 million deaths worldwide were directly or indirectly related to diabetes in the 20–99 years age range. It was the seventh foremost cause of death. The global healthcare expenditure for patients with diabetes was estimated to be USD 850 billion in 2017. (6) It has been also observed that seven out of top ten countries with the largest number of diabetic patients are low or middle-income countries, including India, China, Russia, Brazil, Pakistan, Indonesia, and Bangladesh, among which the prevalence rates are 12.1% and 9.7% in India and China, respectively. (7)
Prevalence in china
The estimated prevalence of diabetes among a representative sample of Chinese adults was 11.6% and the prevalence of prediabetes was 50.1%. Projections based on sample weighting suggest this may represent up to 113.9 million Chinese adults with diabetes and 493.4 million with prediabetes. Unfortunately these findings indicate that diabetes is a major public health problem in China. (8)
Complications of diabetes
The complications of diabetes mellitus affect mostly every tissue of the body and diabetes mellitus is a leading causative factor of cardio- vascular morbidity and mortality, blindness, renal failure, and amputations. (9) This can be broadly classified as micro vascular and macro vascular complications. The micro vascular one can be further divided into diabetic retinopathy/nephropathy/neuropathy and the macro vascular one into stroke, cardiovascular disease.
A brief history of anti diabetic drugs
During the last 90 years, there are around 11 different categories of medications used for the treatment of hyperglycemia in diabetic patients. In the last 30 years, new insulin analogs, glucagon-like peptide 1 agonists, and valuable oral hypoglycemic agents have been introduced. (10) In 1993, the results of the Diabetes Control and Complications Trial (DCCT) were released, followed by the publication of the United Kingdom Prospective Diabetes Study (UKPDS) in 1998. These trials gave in to the consequence that a regulation on the glycemic level contributed to reduce incidence of some of diabetic complications in type 1 DM (T1DM) and T2DM, respectively. Another important aspect was to explore the effect of rapidly securing tight glycemic control in patients with T2DM and high cardiovascular risk. This was the aim of 3 trials, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Veterans Administration Diabetes Trial (VADT) and the Action in Diabetes and Vascular Disease (ADVANCE). (11)
Another important issue is the fact that rosiglitazone was associated with an increase in the risk of myocardial infarction and in the risk of death from cardiovascular causes that had borderline implication. (11) Furthermore due to this, in 2008, FDA published a guidance for the drug industry recommending that new drug applications (NDAs) for diabetes should include evidence that the therapy does not increase the risk of cardiovascular events.
Pathogenesis of diabetes: Triumvirate and ominous octet
The triumvirate of hyperglycemia constitutes of the three factors namely impaired insulin secretion, increased HGP, and decreased glucose uptake. It is henceforth perceived that the β-cell failing occurs much prior to the actual diagnosis and is more serious than previously anticipated. In addition to the muscle, liver, and β-cell, the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all perform meaningful roles in the progression of glucose intolerance in type 2 diabetic individuals. Simultaneously, these eight components amount to the ominous octet and dictate that: 1) amalgamation of multiple drugs used will be imperative for the correction of the multiple pathophysiological defects, 2) treatment should be comply to ease upon the reversal of known pathogenic abnormalities and not only on reducing the A1C, and 3) therapy must be initiated earlier to prevent/slow the progressive β-cell failure that previously is well established in IGT subjects. A treatment paradigm shift is essential in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has anti atherogenic effects), a thiazolidinedione (TZD) (which boost insulin sensitivity, conserves β-cell function, and strive anti atherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are co related with a progressive rise in A1C and gradual loss of β-cell function. (12)
Treatment
Proposed elementary therapy ordinarily comprises lifestyle management and patient education joined with metformin therapy. Although metformin is extensively acknowledged as the favorable medication for the initial treatment of type 2 diabetes (T2DM), there is nevertheless a noticeable concern and lack of unanimity regarding the option of supplementary agents that require to be combined to metformin to enhance glycemic control (13). Other oral hypoglycemic agents constituted also of sulphonylureas such as glipizide, glimepiride, and glyburide that prompt the elevated secretion of insulin. Moreover, insulin, as injection, might be introduced in the initial phase of diabetes, on the basis of the number of liabilities the patients may have and the progression/deterioration of the diabetic stage. New anti-diabetic drugs that have minor risk of hypoglycemia and weight gain support optimal control of glycaemia and reduce insulin necessity in patients with established disease (14)
Contemporary improvements in the treatment of diabetes have stipulated supplementary alternatives for the regulation of diabetes mellitus. Incretin-based therapy is one of the new progresses that trigger insulin secretion and reduce glucagon secretion, resulting in reduction of hepatic glucose production. (15) There are two category of drugs established on the incretin system: GLP-1 receptor agonist, such as exenatide and liraglutide and DPP-4 inhibitors that hamper endogenous degradation of GLP-1 inhibiting DPP-4 (16). There are global ambiguities and disputation as regards to the usage of such therapies, therefore more evidence of the efficiency and safety assurance of incretin-based agents is needed for its future use. (17)
Inhibition of renal glucose reabsorption is another favorable treatment entity to be discussed further. Sodium glucose co-transporters 1 (SGLT1) enact imperative task in the intestinal absorption of glucose and the renal reabsorption of glucose, notably in patients with uncontrolled diabetes and those receiving SGLT2 inhibitors. Subsequently, the inhibition of SGLT1 transporters may illustrate an intriguing therapeutic opportunity to patients with diabetes. The inhibition of SGLT1, either solely or conjointly with SGLT2 inhibition, effectively alter glycemic control in patients with diabetes. (18) They have also shown to reduce CV as a risk factor, obviously lowers blood glucose levels, increases urinary caloric loss with reductions in body weight, lowers BP and volume-overload via osmotic diuresis and natriuresis, decrease LV mass, LV stress, arrhythmia, and HF alterations in tubuloglomerular feedback, and improve renal function via decrease in glomerular hyper filtration. In spite of this, supplementary studies are required to delineate the long-term efficiency and safety of the interventions that target SGLT1.
Nowadays, in clinical practice, insulin treatment is introduced late and then continued thereafter. The natural history of type 2 diabetes is characterized by progressive deterioration of beta-cell functioning leading to worsening of glycemia. Interestingly, the temporary use of intensive insulin treatment may offer long-term beneficial effect on beta-cell function and glycaemic control in newly diagnosed type 2 diabetes. Whilst the practice of using insulin as a long-term therapy has not demonstrated to stipulate clinical worth outside the limits of glycaemic control, early TIIT has effectively established for speedily achieving glycaemic targets and allowing long-term preservation of normoglycaemia with lifestyle management alone in about 50% of people with newly diagnosed T2DM and hyperglycaemia. Furthermost, the earlier use of insulin in the treatment paradigm as second-line therapy is commended, as this scale down the risk of hypoglycaemia following the inclusion of insulin in comparison to later addition of insulin, as well as allowing further β-cell rest, which safeguards β-cell function for the longest attainable time. (19)
Bariatric surgery is an influential weaponery against serious degree of obesity and type 2 diabetes mellitus. The gastrointestinal tract serves as a substantial target to treat T2DM. Surgical operations with intestinal diversion have persistently demonstrated the ability to enhance glucose homeostasis by modulating gut hormones, beyond diminishing energy intake and body weight. LAGB, SG, RYGB and BPD are the four optimal standardized surgical interventions. (20) According to recently published guidelines, bariatric surgery should be advocated in diabetic patients with class III obesity, regardless of their level of glycemic control, and patients with class II obesity with inadequately controlled T2DM despite lifestyle and optimal medical therapy. Surgery should also be considered in patients with class I obesity and inadequately controlled hyperglycemia despite optimal medical treatment. (21) For metabolic surgery to become part of routine diabetes care, the surgical and non-surgical communities will necessitate to study the data without prejudice and yield the strengths, weaknesses and favorable circumstances, because, although there is a wealth of new and high-quality technology in this particular field, the number of patients receiving surgery as a treatment for diabetes remains unfortunately low. (22)
Prevention
Diabetes prevention is the ultimate aspect of public health for the policy makers to emphasize on so as to decrease the worldwide growth of diabetes-related morbidity and mortality. Firstly, the lifestyle factor correlation is of great importance. There are a wide variety of lifestyle factors related to the development of T2DM, such as sedentary lifestyle, physical inactivity, smoking and alcohol consumption (23)
It is customarily postulated that energy-dense Western style diets in conjointly with a sedentary lifestyle are the primary originator of T2D. These two factors are also guarded answerable for the current global epidemic of obesity, which is intimately affiliated with the ascending rate of T2D. Epidemiological studies indicate that high versus low total physical activity is conjoined with a minimization in relative diabetes risk by approximately 30%. All types of leisure time physical activities as well as occupational physical activity acquired to be inversely associated with diabetes risk. Increased duration of sedentary behavior may increase by two fold the diabetes risk. (24) One study showed that every kilogram of weight lost was associated with an additional 7% decrease in risk of progression to diabetes. Combined diet and physical activity programs and use of insulin-sensitizing and weight-loss medications attain the greatest diabetes risk reductions. Physiologically, it has been shown that losing weight depletes free fatty acids from both muscle and liver, resulting in improved insulin sensitivity and glucose homeostasis. (25)
The Diabetes Prevention Program
The most convincing documentation for diabetes prevention emerges from the Diabetes Prevention Program (DPP). The DPP indicated that an intensive lifestyle intervention could lower the incidence of type 2 diabetes by 58% over 3 years. Follow-up of three large studies of lifestyle intervention for diabetes prevention sustained reduction in the rate of conversion to type 2 diabetes: 43% reduction at 20 years in the Da Qing study, 43% reduction at 7 years in the Finnish Diabetes Prevention Study (DPS), and 34% reduction at 10 years and 27% reduction at 15 years in the U.S. Diabetes Prevention Program Outcomes Study (DPPOS). The two major goals of the DPP intensive, behavioral, lifestyle intervention were to achieve and maintain a minimum of 7% weight loss and 150 min of physical activity per week similar in intensity to brisk walking. (26)
Risk factors for diabetes
Patients with known history of atherosclerosis and vascular disease, prediabetes (IFG and/or IGT), genetic predisposition, positive family history in first-degree relatives and high-risk ethnicity (Asians, indigenous populations) are at higher risk for diabetes. (27) Also, phenotypes of insulin resistance, obesity and/or metabolic syndrome, women with GDM or PCOS, men with low testosterone level, hypertension and fatty liver (28)
Conclusion
Diabetes is a complex disease with interplay between genetic and environmental factors. There is a vast ocean of study that has to be conducted to arrive at a desirable optimum target which is to prevent those who are likely to be affected, cure and rehabilitate those who are already affected with it. At this instance, focus should ideally be on the prediabetic patients, and screening for and treatment of modifiable risk factors for cardiovascular disease can be done. Diabetes self-management education and support programs may be appropriate for people with prediabetes to receive education and support to develop and maintain behaviors that can prevent or delay the development of diabetes.