Advances in the Diagnosis and Monitoring of Type 1 Diabetes Mellitus

Lakshmi Vaswani

Published on: 2018-12-28

Abstract

The increased incidence of non-communicable diseases like Diabetes, with its associated mortality and morbidity rates has forced the healthcare community to come up with more innovative ways to deal with it. Type 1 Diabetes has always been an area of interest as the cause of the autoimmune reaction can be attributed to multiple genetic and environmental factors. This review of literature aims to trace the origins of Type 1 Diabetes and examine novel methods in the diagnosis and monitoring of patients, ranging from traditional blood glucose levels and glycosylated haemoglobin levels to genetic markers, hormone levels and autoimmune antibody levels. Monitoring and therapeutic interventions have also progressed from syringe and vial administration of glucose to portable Glucometers, insulin pumps and the artificial pancreas device system. The invention of the Non-invasive Blood glucose monitoring system is also underway. Digitalization in healthcare has led to the development of smart phone applications for the logging of health data for diabetic patients leading to more comprehensive electronic health records, which improves care delivery. The advocacy of self-management with the help of health data apps, increased awareness due to diabetic educators, national and international campaigns, and the provision of emotional and psychological support to the patients, has helped to improve compliance to combat the disease. The holistic, multidisciplinary and patient centric methods used to approach the management of Type 1 Diabetes, has shown improved patient outcomes.

Keywords

Type 1 Diabetes; Insulin; Digitization in Healthcare; Glycosylated haemoglobin; Oral glucose tolerance testing; Auto-immune disorders; Hyperglycemia

Introduction

Discovery and spectrum of the disease

Diabetes mellitus is a major public health problem with tremendous medical and economic burdens. It is a leading cause of death, end-stage renal disease, adult blindness, impotence, and non-traumatic lower-limb amputation. People with diabetes are twice as likely to suffer from stroke or from cardiovascular disease, when compared with age-matched individuals without diabetes. Despite recent advances in diagnostic and therapeutic options, the incidence of diabetes continued to rise in 2007. Worldwide, the prevalence of diabetes is projected to reach 366 million people by the year 2030 [1]. Major increases in both macro vascular and micro vascular complications can be projected on the basis of this growing prevalence.
Diabetes mellitus is a complex metabolic disorder associated with an increased risk of micro vascular and macro vascular disease. Its main clinical characteristic is hyperglycemia [2]. It has taken decades for the scientific community to understand the mechanisms that lead to hyperglycemia and the detrimental effect it has on the human body. The identification of insulin as a key player in glucose metabolism was demonstrated in the 1920’s by Banting, Best, Collip and Macleod, who successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreas, earning them a Nobel Prize in 1923[3].
Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge [2]. The next three decades gave rise to exponential progress in the field of immunology that resulted in the discovery of an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin- In the 1980’s , the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. While Type 1 Diabetes (T1D) was caused mainly due development of auto- antibodies to the body’s pancreatic beta cells, leading to decreased or absent insulin production, Type 2 Diabetes (T2D) was caused mainly due to lifestyle factors causing insulin resistance. T1D was also diagnosed in early childhood and adolescence (earning it the term Juvenile Onset / Childhood Onset Diabetes) while T2D was usually detected in adults. Type 1 diabetes has also shown prevalence in two forms , Maturity Onset Diabetes of the Young (MODY, monogenic diabetes syndromes)and Latent Autoimmune Diabetes of Adulthood (LADA) , which can also be misdiagnosed as Type 2 Diabetes and requires comprehensive family history and autoantibody screening. In recent years, however, patients have been exhibiting features of both types of diabetes, making diagnosis and treatment of their condition more of a challenge. In dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent diabetes leading to the formation of the term “insulin resistance”. Further study into the phenomenon of insulin resistance led to the discovery of its role in cardio metabolic alterations like dyslipidaemia, inflammation and high blood pressure. addition, gestational diabetes and impaired glucose tolerance or “pre-diabetes” has also increased in occurrence adding to the spectrum of the disease. Gestational diabetes refers to raised blood glucose values above normal but below those diagnostic of diabetes, occurring during pregnancy. Women with gestational diabetes are at an increased risk of complications during pregnancy and at the time of delivery. They are also at increased risk of type 2 diabetes in future (Tables 1-5).
Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate conditions in the progression from normal blood glucose levels to diabetes. People with IGT or IFG are at high risk of progressing to type 2 diabetes, although this is not inevitable Diseases of the exocrine pancreas like pancreatitis, neoplasia, and Cystic fibrosis, Endocrinopathies like Acromegaly, Cushing's syndrome, Glucagonoma, Pheochromocytoma, Hyperthyroidism, Somatostatinoma, and Aldosteronoma can also cause hyperglycemia. Drugs or chemicals like Nicotinic acid, Glucocorticoids, Thyroid hormone and β-adrenergic agonists have been known to induce symptoms of diabetes, as well as infections like Congenital Rubella or Cytomegalvirus [4].

Epidemiology of Type 1 diabetes

In India, an estimated 7.8% of the population above 18 years of age has raised blood glucose levels or are on treatment for diabetes. This amounts to an estimated 60 million people with diabetes out of a population of over 1.3 billion. Type 1 diabetes is still not very common. However, of the 542 000 children aged up to 14 years with type 1 diabetes in 2015 globally, India had 70 200, the second largest number in the world after the USA [5]. Type 1 Diabetes has always been an area of interest as the cause of the autoimmune reaction can be attributed to multiple genetic and environmental factors. T1D has a strong relationship with HLA/DR and HLA/ DQ genes, most specifically HLA Type 2 on chromosome 6. These alleles can be either predisposing or protective [6]. Recent studies showed that viral infections that could result in diabetes, include enter virus, factors such as decreased levels of vitamin D can also be a risk factor for T1D [7]. “The hygiene hypothesis” is based on converging evidence that suggests that the frequency of T1D is steadily increasing both in industrialized and developing countries [8,9]. This long-standing trend started in the 1970s in industrialized countries, and its current persistence is worrisome. It has led to a high incidence of T1D in certain countries such as Finland, where the disease has indeed become a public health problem. Not only has T1D incidence increased, but it is also affecting younger and younger children (under 5 and even under 2 yr of age, which had not been previously observed) [10]. In addition, childhood obesity leading to increased resistance to insulin, the primary feeding infants with cow’s milk instead of breast feeding may be involved in causing the disease, although evidence supporting this has been controversial [10].

Patho-physiology of Type 1 diabetes

Immune mediated:Type 1 Diabetes is known to occur due to the immune mediated destruction of the Beta cells in the pancreas, resulting in the decreased production of insulin, which is required for the metabolism of glucose. In a susceptible individual, the immune system is triggered to develop an autoimmune response against altered pancreatic beta cell antigens, or molecules in beta cells that resemble a viral protein. Approximately 85% of T1D patients have circulating islet cell antibodies (ICA) and the majority of patients also have detectable anti-insulin antibodies. Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic beta cells [11].

Genetic predisposition:Type 1 Diabetes has been known to manifest in rarer forms, like MODY (Maturity Onset Diabetes of the Young, monogenic diabetes syndrome) and LADA (Latent Autoimmune Diabetes of Adulthood). MODY has been identified as an autosomal dominantly inherited primary defect in insulin secretion and development of insulin resistance. Mutations have been identified in HNF - 1 and 4 alpha, 1 beta and IPF -1, Neuro-D1. MODY is usually considered in patients with suspected Type 1 Diabetes, who are negative for auto-antibodies, and who has detectable levels of insulin and c-peptide, or in a suspected Type 2 Diabetes patient who is not over weight and shows no signs of insulin resistance. LADA is usually diagnosed above the age of 30 years, and is positive for at least one of the auto antibodies (most commonly GAD antibodies or ICA) with low levels of C-peptide. It is also known as Type 1.5 Diabetes.

Environmental or Infective etiology:Data from retrospective and prospective epidemiological studies strongly suggest the involvement of enteroviruses, such as coxsackievirus B, in the development of T1DM. Enteroviral RNA and/or proteins can be detected in tissues of patients with T1DM. Enteroviruses can play a part in the early phase of T1DM through the infection of β cells and the activation of innate immunity and inflammation. Enteroviruses, through persistent and/or successive infections, can interact with the adaptive immune system. Host genes, such as IFIH1, that influence susceptibility to T1DM are associated with antiviral activities. An increased activity of the IFIH1 protein may promote the development of T1DM [12].

Symptoms and Sequelae

Deficiency in the level of insulin leads to an increase in blood sugar or blood glucose level in the blood stream (hyperglycemia). Due to the inadequate conversion of glucose into usable energy, the cells compensate by activating the breakdown of stored lipids (lipolysis and ketogenesis) as a substitute for glucose, leading to the buildup of toxic metabolites, which in turn has its own detrimental effects on the body systems. Extreme insulin deficiency leads to osmotic diuresis and dehydration as well as elevated free fatty acid levels and diabetic ketoacidosis (DKA). Patients may have dry skin and mouth, stomach pain, inability to keep fluids down, shortness of breath, flushed face and a “fruity” odour coming from the mouth. This is considered as a medical emergency and may be life threatening. Muscle wasting is also observed in patients with uncontrolled T1D results from the failure to stimulate amino acid uptake and protein synthesis and inhibit protein degradation [13].
Other symptoms of hyperglycemia include excessive thirst, polyuria, feeling tired and lethargic, always feeling hungry, having cuts that heal slowly, itching, skin infections, blurred vision, unexplained weight loss, mood swings, headaches, dizziness and leg cramps. Progressive and uncontrolled hyperglycemia will lead to Diabetic Retinopathy, Diabetic Nephropathy and Cardiovascular disease

Diagnosis

The diagnosis of diabetes lies in the determination of hyperglycemia, or more than normal levels of glucose in blood or urine.

Blood and urine glucose levels:Diabetes is a disease that has been known in human history from as far back as 400 BC, since Charaka mentions the discovery of “madhumeha” or “sweet urine”. This sweet urine used to attract ants, which is how medicine men in those times identified a person suffering from diabetes. This is the first invitro test described for diabetes in medical literature. Qualitative tests for urine sugar were perfected by Hermann Fehling in 1848 and semi quantitative test was discovered by Stanley Benedict in 1908. This was followed by the Folin Wu method in the 1940’s, the Nelson-Somogyi method in the 1950’s and the Orth-Toludine method in the 1960’s. The establishment of the Glucose Oxidase Peroxidase method (GOD-POD) enzymatic method, as the gold standard in the 1990’s, was succeeded by the Hexokinase Enzymatic method in the early 2000’s, which is the principle used for glucose estimation in most automated analyzers. The measurement of glucose levels in blood can be done at various times in order to arrive at a diagnosis.

  • Fasting and Post prandial blood sugar and urine tests.
  • Random blood sugar test.
  • Oral glucose tolerance test ( samples are taken at fasting , as well as 2 hours after consumption of 75 g of anhydrous glucose in 250-300 ml of water , and tested).

Although initially glucose monitoring was done through the collection of a peripheral vein sample, the advent of Point of Care testing systems has made the monitoring of glucose levels convenient for patients. It has also helped patient compliance with treatment and follows up.

Glycosylated haemoglobin (HBA1C): The estimation of blood and urine sugar has its drawback in the fact that the test is specific to the amount of glucose present in the blood only at the time of drawing the blood. A glucose level in the blood varies widely according to time and is highly dependent on any recent food intake. To get a more accurate representation of the patient’s status, HBA1C testing was introduced, which estimates the amount of glucose attached to haemoglobin in red blood cells, during the red cells lifespan of 120 days. The value of the HBA1C is expressed as a percentage of the total haemoglobin. This value is unaffected by recent food intake or fasting status, the sample collected is more stable and shows low intraindividual variation. As per the recommendations of the American Association of Clinical Chemistry and the American Diabetes Association HBA1C level is the preferred method for the initial diagnosis of diabetes mellitus.
The main methods by which estimation of glycosylated haemoglobin is done are:

  • Column Chromatography
  •  Affinity Chromatography based Point of care testing systems (cartridge based analysers)
  • High performance liquid chromatography systems (HPLC) , which constitutes nearly 40% of HBA1C testing , due to its specificity and quality of results, the fact that commercially available controls can be used to check precision , and that automated analyzers allow for single tube direct sampling and bi-directional interfacing with LIS ( laboratory information systems) . The other methods of HBAIC estimation, requires an additional step for making a hemolysate from whole blood, (whether manually or through onboard lysing functions in current biochemistry analyzers) which increases turnaround time for result delivery.
  •  Immunoturbidometry reagents and systems (IT). This is based on the principle of latex based agglutination and can be performed on semi-automated or fully automated systems, leading to reagent based and cartridge based nephelometry systems.
  • The American Diabetes Association (ADA) in the 2018 edition of “Standards of Care” for diabetes,emphasizes that health care providers need to be aware of these limitations, to use the correct type of HBA1C test and to consider alternate diagnostic tests (fasting plasma glucose test or oral glucose tolerance test) if there is disagreement between HBA1C and blood glucose levels [14].

Insulin levels, fasting and post prandial:Insulin levels are used to determine if a patient is insulin resistant, in pre-diabetic stage progressing towards Type 2 Diabetes, or in the diagnosis of insulinomas. It also used to monitor a patient on insulin therapy to check therapeutic efficacy, or to investigate cases of hypoglycemia. In addition to the routine tests for diabetes, tests for cholesterol, ferritin, micro albumin or creatinine may also be done, in order to detect complications of progressive diabetes if any. Routine eye examinations for diabetic retinopathy may also be advised, and work up for diabetic nephropathy or diabetic foot may also be done.

Tests done to screen specifically for type 1 diabetes
C-Peptide
levels:
C-peptide is a widely used measure of pancreatic beta cell function. It is produced in equimolar amounts to endogenous insulin but is excreted at a more constant rate over a longer time. Methods of estimation include un-stimulated and glucagon stimulated and mixed meal stimulated serum sampling (fasting and random) as well as 24 hour and random urinary sampling and Urinary c-peptide creatinine ratio (UCPCR). Modern assays detect levels of c-peptide which can be used to guide diabetes diagnosis and management. . In healthy individuals the plasma concentration of c-peptide in the fasting state is 0.3-0.6 nmol/l, with a postprandial increase to 1-3 nmol/l [15]. Specifically a c-peptide level of less than 0.2 nmol/l is associated with a diagnosis of type 1 diabetes mellitus (T1DM). C-peptide level may correlate with micro vascular and macro vascular complications and future use of insulin therapy, as well as likely response to other individual therapies. C-peptide is a useful tool in the classification of diabetes, differentiating between the various presentations of diabetes. C-peptide is associated with duration of disease as well as age of diagnosis. Whilst c-peptide is useful in classifying diabetes it must always be interpreted in clinical context of disease duration, co morbidities, and family history.

Autoantibody Screening and detection:Clinically, Islet antibodies (iAb) are best known for their role in confirming the diagnosis of Type 1 Diabetes, where the presence of one or more iAb indicates pancreatic autoimmunity, responsible for pancreatic beta cell destruction and reduction or absence of insulin secretion [16]. Autoantibody detection and quantification is done by fluid-phase radioimmunoassay, bridge-ELISA and electrochemiluminescence detection (ECL).
The most common types of auto-antibodies detected are:

  •  Insulin Auto Antibodies (IAA)
  • Insulinoma Associated 2 Autoantibodies (IA 2 )
  •  Islet cell Cytoplasmic antibodies (ICA)
  •  Glutamic Acid Decarboxylase Autoantibodies (GAD-A)
  • Zinc Transporter 8 Autoantibodies (ZT8-A)

Beyond confirming their diagnosis of T1D, clinicians often order autoantibodytesting to help differentiate T1D from type 2 diabetes (T2D), as well as MODY. Clinicians also must rely on iAb when clinical and metabolic markers such as age, pubertal status, sex, body mass index, HbA1c, and family history do not readily help with the differential diagnosis. In newly diagnosed cases of T2D in adults, approximately 10% of patients are positive for a single iAb, predominately GADA. These patients, who also progress slowly to needing insulin, often receive a LADA diagnosis. Given the phenotypic variability of LADA-diagnosed patients in combination with the presence of iAb, LADA most likely is not a distinct entity but rather a slowly progressive form of autoimmune T1D [16]. More recently, auto-antibodies to Pdx1 and Reg1A have been demonstrated with reported prevalence of 24% and 47%, respectively. In both cases, the targets were identified by probing Western blots with sera from diabetic patients [17].

Monitoring And Management Of Type 1 Diabetes

Metabolic management

Traditional methods of managing and treating patients with Type 1 Diabetes involved regular monitoring of blood sugar levels and delivery of insulin, either through syringe and vial or through an insulin pen as part of a multiple daily injection (MDI) regimen. The introduction of Lispo and Aspart insulin (rapid acting insulin analogues) and glargine insulin (long acting insulin) has made the process a little easier for patients on lifelong therapy, helping to reduce risk of hypoglycemia. Patients on insulin need to be educated about matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age [15].
Pramlintide (an amylin analogue) may be considered for use as adjunctive therapy to prandial insulin in adults with type 1 diabetes failing to achieve glycemic goals. Evidence suggests that adding metformin (biguanide) to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients and poorly controlled adolescents with type 1 diabetes, but evidence from larger longitudinal studies is required. Current type 2 diabetes medications like GLP-1 agonists ( glucagon-like peptide-1), DPP-4 inhibitors(dipeptidyl peptidase- 4) and SGLT2 inhibitors (Sodium-glucose co-transporter 2) may be potential therapies for type 1 diabetic patients, but require large clinical trials before use in type 1 diabetic patients [18]. This method of management is painful, inconvenient and often traumatic for patients suffering from this disease. This is led to lower patient compliance to treatments and follow up which has caused the healthcare and pharmaceutical industry to innovate new ideas and technologies for more effective and hassle free management methods, in order to deal with the rising rates of patients suffering with the disease.
This lead to the introduction of Real time Continuous Glucose monitoring Systems (RT CGMS), through Glucometers as a point of care system. Not long after came the invention of a Continuous Subcutaneous Insulin Infusion Therapy (CSIIT) or an artificial pancreas device system. This is a system of devices that closely mimics the glucose regulating function of a healthy pancreas. It consists of three types of devices i.e. a continuous glucose monitoring system (CGM) and an insulin infusion pump. A computer controlled algorithm connects the CGM and insulin infusion pump to allow continuous communication between the two devices. The system is a closed loop system or an automated insulin delivery system or an autonomous system for glycemic control. The system will not only monitor blood glucose levels in the body, but it will automatically adjust the delivery of insulin to reduce hyperglycemia and reduce incidents of hypoglycemia with minimal input from the patient. It helps to maintain target HBA1C values as well. The dose of insulin is delivered as per a controlled algorithm rather than a pre-determined or pre-timed dose. Routine blood sugar monitoring is necessary in order to check the adequacy of the dose and indicate the need to change it if required.
Maintenance of appropriate HBA1C values and minimization of hyperglycemic excursions are difficult for many Pediatric patients with type 1 diabetes. While HBA1C and blood glucose targets are needed, the ADA emphasizes that glycemic targets should be individualized with the goal of achieving the best possible control while minimizing the risk of severe hyperglycemia and hypoglycemia. Continuous glucose monitoring (CGM) sensor-augmented pump (SAP) therapy is an alternative to multiple daily injection (MDI) therapy in this population. Sensor-augmented pump therapy for HBA1C reduction (STAR 3) was a 1-yr trial in 2011 that included 82 children (aged 7-12) and 74 adolescents (aged 13-18) with A1C values ranging from 7.4 to 9.5% who were randomized to either SAP or MDI therapy. Compared with the MDI group, subjects in the SAP group were more likely to meet age-specific A1C targets. Glucose variability improved in the SAP group compared to the MDI group. Children wore CGM sensors more often and were more likely to reach age-specific HBA1C targets than adolescents. SAP therapy allows both children and adolescents with marginally or inadequately controlled type 1 diabetes to reduce A1C values, hyperglycemic excursions, and glycemic variability in a rapid, sustainable, and safe manner [18].

Self-management

The current approach to diabetes self-management education (DSME) interventions is usually based on a short-term program with or without some degree of follow-up. This approach can be conducive to the initial acquisition of basic diabetes self-management skills (DSMS). However, to effectively manage diabetes over a lifetime, programs are needed that support the continued enhancement of self-management skills, behavioural strategies, social support, and metabolic improvements following DSME. Such interventions need to reflect the dynamic and evolving conditions of patients “real-world” environment and life circumstances. Instead of trying to fit patients into predetermined self-management interventions, flexible self-management interventions that are responsive to the unique and individual lives of patients are needed. This support structure should be equally accessible to all patients regardless of economic, social, and environmental circumstances. Diabetes education has changed a great deal in recent years. One important change has been the increased emphasis on patient-centred or collaborative approaches to care and education [19] (Figure 1).

There is also a requirement for a plug in role between the patient and the doctor, that of a Diabetic educator, who could walk a patient through his diagnosis and treatment plan, with a personalized approach. The introduction of Diabetic Educators in the health system has reaped benefits in the form of better patient compliance, patient engagement, community awareness and improved outcomes. Patients have constant emotional support and access to medical advice whenever needed without the inconvenience or expense of regular physician visits. The American Association of Diabetic Educators launched its website in 2018, and the Indian Diabetic Association (IDA) also has certifications in Diabetic education.

Nutritional therapy

Individualized medical nutrition therapy is recommended for all people with type 1 diabetes as an effective component of the overall treatment plan. Monitoring carbohydrate intake, whether by carbohydrate counting or experience-based estimation, should be done. If adults with type 1 diabetes choose to drink alcohol, they should be advised to do so in moderation keeping in mind potential interactions with medications.

Physical activity or exercise

Exercise should be a standard recommendation as it is for individuals without diabetes; however, recommendations may need modifications due to the presence of macro- and micro vascular diabetes complications. Exercise creates challenges for people with type 1 diabetes due to the increased risk for both hypoglycemia and hyperglycemia. During exercise, multiple hormones (insulin, glucagon, catecholamines, growth hormone, and cortisol) control fuel metabolism and create a balance between glucose uptake by exercising muscles and hepatic glucose production. The equilibrium between insulin secretion and the counter-regulatory hormones varies according to the exercise type, intensity, and duration (Figure 2). Patients of all ages (or caregivers of children) should be educated about the prevention and management of hypoglycemia that may occur during or after exercise. Patients should be advised about safe pre-exercise blood glucose levels (typically 100 mg/dL or higher depending on the individual and type of physical activity). Reducing the prandial insulin dose for the meal/snack preceding exercise and/or increasing food intake can be used to help raise the pre-exercise blood glucose level and reduce hypoglycemia. A reduction in overnight basal insulin the night following exercise may reduce the risk for delayed exercise-induced hypoglycemia. SMBG should be performed as frequently as needed (before, during, and after exercise) in order to prevent, detect, and treat hypoglycemia and hyperglycemia. Sources of simple carbohydrate should be readily available before, during, and after exercise to prevent and treat hypoglycemia.

Immunotherapy

Therapy trials to prevent type 1 diabetes development (prevention), to preserve remaining β-cells (preservation), and to replace β-cells (transplantation) are on-going. Although means are available to screen and predict family members at risk for developing type 1 diabetes, efforts to delay or prevent disease onset have been largely disappointing [20]. Immunomodulation has emerged as a form of therapy which aims to restore self-tolerance, resulting in the down regulation of autoimmune responses to pancreatic self-antigens and arrested on-going β-cell destruction. When combined with replacement of the lost insulin-producing cells, this may lead to the restoration of euglycaemia
[18]. A variety of different immune modulatory and immune-suppressive agents have been evaluated in patients with recent-onset type 1 diabetes, and the effects have been modest at best: for the subset of drugs that appear to have an effect, not all patients respond; for those who do, the effects are generally transient. Many of the agents tested to date are FDA approved for other indications, but given the observations to date and potential toxicities, the recommendation is that patients should only receive these drugs after being enrolled in clinical research protocols with appropriate follow-up. Long-term safety and efficacy data are scarce, especially in children. Investigators continue to evaluate promising new agents and combinations of drugs or cell-based therapies in an effort to safely and effectively modulate the autoimmune response [20].

Beta cell replacement therapy

β-Cell replacement therapy may be achieved through pancreas or islet transplantation in select candidates. Pancreas transplants are now accepted as a proven therapy, while islet transplants, though significantly improving, are still mostly done on an experimental basis.

Pancreas transplants

Pancreas transplants are most often performed in combination with kidney transplantation, either as a simultaneous pancreas-kidney (SPK) transplant or as a pancreas-after-kidney (PAK) transplant [21]. SPK and PAK transplants may be considered for individuals with late-stage kidney disease because the transplants can normalize glucose levels, which will prevent hypoglycemia and provide some protection for the transplanted kidney [22], and provide other benefits, including an improvement in quality of life [21]. These recipients will already require immunosuppression for their renal transplants, which means the major additional risk, is the operative procedure. SPK transplants function for an average of 9 years, compared with 6 years for PAK transplants [21].

Application of technological advancements

The rising numbers of patients affected with non-communicable diseases especially diabetes has called for a more holistic approach to care delivery for these patients which spans from prevention to education and spreading awareness, to diagnosis and management, as well as emotional support and facilitating access to services or treatments required. This calls for agents or representatives from various industries to work together, to improve patient outcome. Technology plays a large role in helping with lifestyle modification by providing space and facility to log health data, helping patients to set goals and track their progress, Demming’s mantra,” what can be measured can be improved” is applied to patient goals to maintain a health HBA1C or glucose level. With the rapid digitalization of healthcare came the next step in self-management, which was the automatic logging of Glucometers and CSIIT data into a cloud based system, or even in smart phones, to improve communication between doctors and patients. This data could also be added to the patient electronic health records (E-HR) to get more comprehensive history from patients. Widely used health data applications available both on IOS and Android software’s are My Sugr, which enables patients to log their data in the form of insulin or drug dosages and timings , meal times and caloric intake, syncs with other health or fitness applications for physical activity data and even syncs with a Glucometers (Accucheck) for glucose levels as well as an estimated HBA1C level ( which has to be verified by levels from traditional blood draws) Other popular applications include Sugar Sense, Health 2 Sync, Diabetes Connect and Glucose Buddy.

While some of the technology being used currently has already been approved by the FDA after being vetted through extensive clinical trials the market for new methods to improve patient care in this area is growing. There are advanced technologies in the pipeline, with prototypes developed and under trial, expected to launch in the coming years. One of the more exciting innovations is the Non Invasive Blood Glucose Monitoring system, which aims to provide a way to measure circulating capillary blood glucose without having to undergo repeated finger pricks or blood draws. This has often been cited as the “Holy Grail “of glucose device inventions. Epic Health App has introduced software that makes it possible for a patient to place a fingertip on the lens of the camera of a smart phone, which in turn captures a series of images and with the help of transdermal measurement through sensor pads and infra-red spectroscopy, can capture variations in temperature, blood pressure and heart rates, 

blood sugar concentration and insulin resistance. The struggle since 2014 is to manufacture a commercially available and clinically reliable device, which can then be linked to smart phone applications to provide intelligent analysis and forecast trends in blood glucose levels. This has led to patients regaining control of their health and their bodies, which has helped them to mentally and psychologically deal with the impact of handling the disease and its progression. Self-management with the use of advanced technology and tools has helped to improve patients’ lifestyles and decrease their dependency on hospital or lab visits. It enables them to maintain strict glycemic control and ensures better compliance to treatment options.

Barriers to using digital tools for diabetes management

  • Cost: A potential barrier to any new medical technology is the cost. In addition, the use of apps requires the person to use an expensive smart phone and internet availability which may not be prevalent in rural areas.
  • Insufficient scientific evidences: Despite increased enthusiasm with the use of digital tools for diabetes self-management, the evidence for safety, efficacy, and cost-effectiveness of these tools are largely unknown. Most of the studies on effectiveness of apps or internet-based tools for diabetes self-management were underpowered to see a meaningful and statistical difference and were of short duration. In addition, source information available on the blogs or through social media that are not regulated may not be scientific and may mislead patients. Similarly, most of the nutrition and physical activity related mobile apps have not been evaluated for the accuracy of information or measures. Large randomized controlled trials of long duration are necessary to establish the safety, efficacy, and cost-effectiveness of apps in diabetes self-management.
  • Not useful in certain populations: Most available apps may not be useful for the elderly, non-English speakers, physically challenged, and subjects from a lower socio-economical status.
  • Data protection: With the increasing use of electronic health records, digital tools, smart watches, and apps, we generate a large amount of data that is stored on servers. There are a few problems with sensitive data storage by the institutions or governments wanting to store health records or national records. If the data is collected in one country and stored on the server in other country, a whole different set of legal rules might be enforced. In addition, there is a growing controversy on who owns the data: patients or the device or software owner.

Data security: Certain devices such as an artificial pancreas (e.g. insulin pump, CGM and blood glucose meter) are connected via Bluetooth. Wireless communication can be intercepted by electromagnetic devices or hacked by cyber

  • This poses significant risks to a person using such devices for diabetes management.
  • Regulatory barriers: Although the use of digital tools is helpful in the self-management of diabetes, improper use of digital tools or technical issues with the algorithms or software can lead to undesirable side effects. For example, insulin dose calculator software is helpful for patients with diabetes to determine bolus insulin doses. The technical problem can result in higher insulin dose calculation and can result in severe hypoglycemia. Considering the increasing use of digital health and its potential harms, the FDA issued a guideline for app and health software developers. As recommended by the FDA, any computer- or software-based devices (including apps) intended to be used for the electronic transfer, storage, display, and/or format conversion of medical device data is considered a Medical Device Data Systems (MDDS) and they are classified in three different classes [Class III being high-risk to Class I being low-risk] based on the potential risks of using the software or a digital tool. It has been recommended for the software or device developer to follow the regulatory requirements such as Establishment registration, Medical Device listing, Quality System (QS) regulation, Labelling requirements, Medical Device Reporting, and Reporting Corrections and Removals depending on the device or software risk. Similarly, the European Union has also issued a regulatory framework for the use of mobile health devices.

Development of national campaigns to create awareness

The international Diabetes Federation (IDF) has built the foundation for the Indian Diabetic Association (IDA), which helps with the establishment of diabetic care units in hospitals and health centres, camps, outreach programs and patient education. The Research Society for the Study of Diabetes in India has released the “Indian Guidelines for the management of Diabetes Mellitus” in 2018. The Indian Council of Medical Research is actively involved in the development of new treatment modalities for diabetes and the WHO has identified WHO Collaborative Centres nationwide for the Prevention and Control of Non Communicable Diseases.

Dealing with the psycho-social aspect of type 1 diabetes

India is dealing with an increasing number of patients with diabetes, yet it is also struggling with the lack of awareness about the disease as well as the social stigma that arises with Type 1 Diabetes in particular, as it affects children and adolescents. In order to combat this, various campaigns have been initiated by private companies, government bodies or NGOs. “Beyond Type 1” is a social media campaign to raise awareness in the global community and acts as a resource and support for patients with the disease. “Diabetes India Youth in Action” (DIYA) is an NGO that aims to spread awareness about the disease and eliminate discrimination in schools, colleges, communities and work places. It is also working to improve the availability of insulin as a lifesaving medication, with coverage 

under national health insurance schemes to reduce the cost to under privileged patients. It also aims to add diabetes to the Government of India Disabilities Act so that patients can obtain support for their condition. The “Mithai Project” run by the Government of Kerala, works for the provision of insulin pumps for children from low income households. “Changing Diabetes in Children Program” (CDIC) and the Indian Diabetes Education Program 2010-2012, aims to improve awareness in both rural and urban areas [23].

 

Tables

Table 1: Genetic or Inherited causes of hyperglycemia.

No

Type of defect

Syndrome/ Condition

 

1.

Genetic defects of β-cell function

 

Chromosome 12, HNF-1α (MODY3)

Chromosome 7, glucokinase (MODY2)

Chromosome 20, HNF-4α (MODY1)

Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4)

Chromosome 17, HNF-1β (MODY5)

Chromosome 2, NeuroD1 (MODY6)

Mitochondrial DNA

 

2.

Genetic defects in insulin action

 

Type A insulin resistance

Leprechaunism

Rabson-Mendenhall syndrome

Lipoatrophic diabetes

 

3.

Uncommon forms of immune-mediated diabetes

 

“Stiff-man” syndrome

Anti-insulin receptor antibodies

 

4.

Other genetic syndromes sometimes associated with diabetes

 

Down syndrome

Klinefelter syndrome

Turner syndrome

Wolfram syndrome

Friedreich ataxia

Huntington chorea

Laurence-Moon-Biedl syndrome

Myotonic dystrophy

Porphyria

Prader-Willi syndrome

Table 2: Factors that affect the interpretation of HBA1C levels.

No

Factors

Increased HBA1C

Decreased HBA1C

 

1

Erythropoiesis

iron, vitamin B12 deficiency

(Decreased erythropoiesis.)

 

Administration of:

1.erythropoietin,

2. iron,

3.vitamin B12,

4. reticulocytosis,

5. Chronic liver disease.

 

2.

Altered Hemoglobin

 

Genetic or chemical alterations in hemoglobin: haemoglobinopathies, HbF, methaemoglobin, may increase or decrease HBA1C

 

3

Glycation

Alcoholism, chronic renal failure, decreased intra-erythrocyte pH.

Aspirin, vitamin C and E, certain haemoglobinopathies, increased intra-erythrocyte pH.

 

4.

Erythrocyte destruction

Increased erythrocyte lifespan; Splenectomy.

Decreased erythrocyte life span: haemoglobinopathies, splenomegaly, rheumatoid arthritis or drugs such as antiretrovirals, ribavirin and dapsone.

 

5.

Assays

Hyperbilirubinaemia, carbamylated hemoglobin, alcoholism, large doses of aspirin, chronic opiate use.

hypertriglyceridaemia.

Table 3: Criteria for the Diagnosis of Diabetes.

Criteria for the Diagnosis of Diabetes

1.        Fasting Plasma Glucose (FPG)  > 126 mg/dl ( > 7.0 mmol/L)

(Fasting defined as no caloric intake for at least 8 hours 

 

2.        2 hours post glucose (2h PG) > 200 mg/dl ( >11.1 mmol/L)

(As per WHO guidelines, using glucose load of 75 grams of anhydrous glucose dissolved in 200-300 ml of water.

 

3.        Glycosylated Haemoglobin   (HBA1C) > 6.5 % (> 48 mmol/mol)

 

4.        Random plasma glucose > 200 mg/dl ( >11.1 mmol/L) in a patient with symtoms of hyperglycemia

Figures

Figure 1: Sequel of type 1 diabetes.

Figure 2: Holistic management of type 1 Diabetes.

Conclusion

Type 1(due to autoimmunity) and type 2 (due to insulin resistance) diabetes is heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classification is important for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both age-groups. In both type 1 and type 2 diabetes, various genetic and environmental factors can result in the progressive loss of b-cell mass and/or function that manifests clinically as hyperglycemia. Once hyperglycemia occurs, patients with all forms of diabetes are at risk for developing the same chronic complications, although rates of progression may differ. An insulin level is usually reduced or absent in type 1 diabetes, with under nourished patients with a moderate genetic predisposition and constitutes 5-10% of diagnosed diabetics. Insulin levels are high but ineffective due to insulin resistance, with obese patients and strong genetic predisposition in type 2 diabetes, making up 90-95% of all diagnosed diabetic cases. Diabetes as a non-Communicable disease is on the rise and the healthcare community requires a multidisciplinary, innovative approach in order to provide patients with the most comprehensive and effective care possible. Traditional testing and diagnosis is giving way to more advanced technology with more emphasis on genetic and metabolic testing. Monitoring disease progression and treatment effectiveness have become more patient-centric, making use of smartphone and application based technology to improve patient compliance. More emphasis has also been put into dealing with the emotional and psychological impact of the disease, along with the scientific cure, in order to combat the disease in a more holistic way. National and International campaigns, committees and organizations are also working to help spread awareness about the disease and its progression in order to allow for early diagnosis and intervention.

Acknowledgements

We thank the staff at Bhatia Hospital Laboratory for general administrative support.

Conflicts of Interest

The authors do not have any conflicts of interest

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