Volume 9, Issue 9, September– 2024 International Journal of Innovative Science and Research Technology

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Diabetes Genetic Epidemiology and Associated

Comorbidities: A Comprehensive Review
1
Dr. Priya Kaushik; 2Dr. Rashmi Nain; 3Dr. Rupali Bains; 4*Dr. Prashant Kumar
All India Institute of Medical Sciences Rishikesh.249201 Uttarakhand

Corresponding Author:- 4*Dr. Prashant Kumar

Abstract:- Diabetes is characterized by elevated blood The hormone insulin, which is secreted by beta cells in the
glucose levels in humans, which are mostly brought on by pancreas, controls a person's blood sugar levels. The
poor insulin production and utilization. Numerous genetic development of diabetes mellitus depends on the processes
factors are responsible for causing TIDM such as PTPN22 that control the mass of beta cells in the pancreas and the
and CTLA. People with diabetes mellitus are more likely release of insulin. Diabetes maturity of the young is a group
to acquire a variety of linked conditions and conditions of single-gene disorders that affect pancreatic-cell function.
known as comorbidities because of a number of Because the consequences of gene mutations in these
hereditary factors, environmental factors, certain illnesses are so severe, diabetes usually appears in childhood
medications, and other causes. Some of the common or adolescence 4. It also causes a number of the body's
comorbidities that are prevalent in the T2DM patient systems to malfunction. Additionally, it demonstrates the
population include congestive kidney disease, harmful effects on the body's many systems, including the
retinopathy, neuropathy, cardiovascular disease, urinary blood circulation and central nervous systems. Diabetes is
disorders, hyperlipidemia, and obesity. Diabetes has a divided into three main categories because of its many causes
high rate of hypertension, obesity, hyperlipidemia, and and manifestations. These are: (T1DM) Insulin insufficiency
cardiovascular disease frequently coexist in patients as is the etiology of type 1 diabetes mellitus, whereas (T2DM)
comorbid conditions. Knowing how genes function differs Insulin resistance, which stops the body from producing
and how particular genetic factors raise the likelihood of insulin, is the cause of type 2 diabetes mellitus. Gestational
comorbidities during diabetes can help develop effective diabetes, which develops during pregnancy, is the cause of
medication for the management of diabetes Insight into type 3 diabetes 5. Out of them, T2DM is the most fatal which
how different genes operate and how specific genetic leads to numerous mortality death.
factors increase the risk of comorbidities during diabetes
can aid in the development of effective diabetic The second most common kind of diabetes mellitus
medications to curb the epidemic of diabetes and its worldwide, type 1 diabetes is characterized by an
associated complications. A multifaceted approach is autoimmune cause, an absolute requirement for insulin, and a
required, including early detection of diabetes, checking typically earlier start4,6. In type 1 diabetes, the condition is
for its consequences, providing the best possible care at all more critical and mostly brought on by auto-reactive T
levels of treatment for those who currently have the lymphocytes on islet beta cells and called an autoimmune
disease, and preventing diabetes in those with attack. When clinical symptoms appear, they are usually
prediabetes. Diabetes prevalence is expected to increase, severe and preceded by rapid metabolic decompensation. It is
which will increase the need for rehabilitation therapy to believed that 70–90% of the beta cell mass has been
decrease any problems the condition can cause. Exercise destroyed7,8. The progressive decrease of beta cell mass and
has been reported to improve insulin sensitivity to function in diabetics is caused by a variety of reasons. The
elevated blood sugar levels, enhance glucose absorption, progressive loss of beta cell mass and function during the
decrease intra-abdominal fat a known risk factor for course of the disease exacerbates the continued deterioration
insulin resistance—and prevent cardiovascular issues. of metabolic control, regardless of the underlying reasons and
pathogenetic pathways. Network theory applied methodically
Keywords:- Diabetes, Epidemiology, Comorbidities, to the metabolic and regulatory mechanisms beneath9 .
Polymorphism, Covid-19 Diabetes. Because the genes linked to monogenic kinds of diabetes fit
neatly into the current models of how biological networks
I. INTRODUCTION may be predicted to function, faking glucose homeostasis
may offer a useful way to prioritize genes for future
Globalization and changes in lifestyle have had a research10–13. The goal of a relatively new field of research
significant impact on politics, the environment, society, and called "genetic epidemiology" is to elucidate the ways in
human behavior over the last fifty years. Both in which genetic and environmental factors combine to produce
industrialized and emerging nations, there are significantly disease in populations. Studies have also been conducted on
more persons with diabetes and obesity 1–3. Diabetes refers to the genetic epidemiology of diabetes. Some of the genes that
the increased blood glucose level in the human body which is cause type 2 diabetes and its related comorbidities are HLA
basically due to impaired production and insulin utilization. and INS, CTLA4, PTPN22, POSTN, and TCFL213,14. The

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ISSN No:-2456-2165 https://doi.org/10.38124/ijisrt/IJISRT24SEP726

complications of both diabetes and hypertension share a lot myocardial infection, coronary artery disease, stroke,
of similarities. There are macrovascular and microvascular peripheral vascular disease and retinopathy, nephropathy, and
diseases among these problems such as heart failure, neuropathy 1,2.

II. GRAPHICAL ABSTRACT Hyperglycemia, lipotoxicity, autoimmunity, inflammation,

adipokines, islet amyloid, and incretins. Changes in
 Activation of the Beta Cell pancreatic beta cells' homeostasis affect the population
Beta cells present in the pancreas help in regulating dynamics and function of these cells because they are so
glucose concentration in blood. Dysfunction and degradation sensitive to blood glucose levels 15. Changes in lipoprotein
in beta cells culminate in diabetes (Figure 1). The functioning profiles are frequently linked to diabetes 16.
of beta cells is influenced by different ways such as

Fig 1 Process of Activation of the Beta Cell.

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In T1DM, autoimmune responses are involved. Insulin estimated that 380 million people worldwide will suffer from
secretion and beta cell mass persistently decline as a result of diabetes in 2025. 85–95% of cases of type 2 diabetes occur in
autoimmune-mediated death of beta cells during the illness17. wealthier countries; in developing countries, this number is
Many scholarly investigations have highlighted the way in much higher 26, 27. The results of the Diabetes Epidemiology
which insulin resistance causes beta cells to proliferate in an Collaborative Analysis of Diagnosis Criteria in Asia
attempt to compensate for insulin insufficiency, ultimately (DECODA) study showed that the age-specific prevalence
leading to beta cell malfunction and failure 18. It is well varied widely among Asian populations. Between the ages of
established that incretin hormones enhance beta cell 60 and 69, diabetes prevalence peaked in Indian populations,
production and function 19,20. Hypersecretion of islet amyloid while between the ages of 70 and 89, it peaked in Chinese
in pancreatic islets has long been known to be a pathological ones. In comparison to Chinese people, Indians have a higher
feature of T2DM, and their connection to beta cell death has age-specific prevalence and earlier onset of poor glucose
been extensively studied 21,22. The "adipose-insular" axis is control 28. In India, it has been noted that young people have
regulated by hormone-like peptides and proteins called a significant prevalence of diabetes with mature onset 29,30.
adipokines. Certain adipokines, such as leptin, function as Statistics from southern India demonstration that between
proinflammatory cytokines and impair beta cells 23,24. 2000 and 2006, the occurrence of diabetes among people
under the age of 44 increased from 25% to 35% 31,32. The
 Prevalence and Global Impact prevalent of obesity and young-onset diabetes has been
Diabetes and its related comorbidities are a foremost exacerbated by quick changes in eating habits, decreased
healthcare problem global and the major challenges faced by physical activity, changing leisure activity patterns, longer
patients, healthcare systems, and national economies. The workdays, and shorter sleep lengths 33–35.
WHO projects that between 2000 and 2030, there will be a
37% increase in the world's population and a 114% increase According to the latest edition of Atlas published in
in the number of diabetics. According to Asian predictions, 2021 by IDF (International Diabetes Federation) 537 million
China and India would have the highest rates of diabetes (49.4 worldwide population is diabetic and it is hypothetically
and 42.3 million, respectively) by 2030. Estimates from 2003 increased to 643 million and 783 million in 2030 and 2045
showed that 314 million people worldwide had impaired (approx. 46%), previously in 2019, the projection was made
glucose tolerance and 194 million adults had diabetes 25. By to 700 million for 2045. The projection was made for the
2007, this prevalence had risen to 60% and 75%, and by 2025, African continent where in the same timeline the projection
they are expected to reach 73% and 80%, respectively. It is is set to 134%.

Fig 2 Number of People with Diabetes in Different years (2011-2021).

 Prevalence of HIP (Hyperglycemia in Pregnancy) (42.3%) in women aged 45 to 49, despite the fact that few
There have been 58 research overall on hyperglycemia pregnancies occur in this age group. Figure 3 shows the age-
in pregnancy (HIP), according to the IDF Atlas 2021. wise prevalence of HIP. In addition, diabetes is more
Estimates indicate that 16.7% of live births to women in 2021 common in non-pregnant women in this age group. Because
entailed hyperglycemia in one form or another. The younger women had higher rates of reproduction, women
frequency of HIP as a percentage of all partum women under 30 accounted for less than half (46.3%) of all HIP cases
increases dramatically with age, with the highest prevalence (9.8 million).

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Fig 3 Prevalence of HIP in Different Ages.

 Diabetes-Related Mortality (Excluding Pandemic) is the equivalent to 12.2% of all deaths in this age group
Globally, diabetes is the leading cause of death. Without worldwide due to all causes. As seen in Figure 4, persons
the mortality risks associated with the COVID-19 pandemic, under 60 who are employed account for more than a third
(6.7) million adults between the ages of 20 and 79 are (32.6%) of all diabetes-related deaths. This is the equivalent
expected to pass away in 2021 from diabetes or its of 11.8% of all deaths globally among those under the age of
consequences, according to the data in IDF Atlas 2021. This sixty.

Fig 4 Diabetes-Related Mortality.

 Economic Impact of Diabetic International Diabetes Federation Diabetes Atlas, since its
Diabetes significantly increases the cost of healthcare third edition in 2006, the health costs associated with diabetes
for entire countries, as well as for those who have the disease have climbed from USD 232 billion (2007) to 966 billion
and their families. The term "Direct Cost" refers to all medical (2021) for a person aged 20 to 79. Over the past 15 years, this
expenses related to diabetes, whether they are paid for out of has increased by 316%. The estimates of health expenditure
pocket to people who suffer from diabetes or by private, related to diabetes up to 2045 as per the analysis done by IDF
public, or governmental payers. According to the are given in Figure 5.

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Fig 5 Total Diabetes-Related Health Expenditure for Adults (20–79 years) with Diabetes from 2011 to 2045.

 Genetic Epidemiology and Polymorphism connected41. Some genes are affected and result in T2DM
Positional cloning, linkage mapping, and candidate gene such as ABCC8 (ATP-binding cassette, subfamily C;
studies have advanced most rapidly in the types of diabetes sulfonylurea receptor), which is responsible for the regulation
with the simplest genetic models. Early research describing of potassium channels and insulin release), Calpain 10 is a
diabetes caused by mutations in the mitochondrial genome protease and glucagon receptor that regulates hepatic glucose
(World Health Organization, 2021), insulin (INS), and insulin production and insulin secretion, Glucokinase aids in the
receptor 36, genes offered crucial insights into glucose metabolism of glucose, KCNJ11 (Potassium inwardly-
homeostasis. The balance between insulin action and rectifying channel, subfamily J, member 11), which regulates
production, which is controlled by cell mass and/or function, the secretion of insulin, PPARG (Peroxisome proliferator-
is known as glucose homeostasis. The most susceptible activated receptor γ) and HN4FA (Hepatocyte nuclear factor
genes/proteins to deteriorating the system are those found at 4 α) are transcription factors, SLC2A1 (Glut 1) which a
hubs that are most densely interconnected. Therefore, it may glucose transporter 13. POSTN and TCFL2 genes are
be more likely that genetic diversity at hub genes will result responsible for T2DM and its associated comorbidities like
in observable changes in glucose homeostasis 37. T1D stands obesity, heart diseases, asthma, cancer, and hypertension.
out in comparison to other complex illnesses because of the OSF-2 (Osteoblst-specific factor) is a protein that facilitates
extent of ancestral threat connected to a sole locus, the HLA the adhesion and migration of epithelial cells with the help of
(Human Leukocyte antigen). Even though there is compelling alpha-V/beta-3 and 5 integrins ligands 14. TCFL2
evidence linking some other autoimmune illnesses to the (Transcription factor 7 like 2) is a protein acting as a
HLA region 38.HLA was first identified as a potential gene transcription factor encoded by the TCFL2 gene located on
through association studies, and the evidence for a linkage at chromosome 10q25.2-q25.3, which comprises 19 exons.
HLA in T1D is stronger than that reported for a linkage in any TCF7L2 is an associate of the TCF family and has an impact
other complex disorder 38. ..A region known as PTPN22 on several biological pathways, including the Wnt signaling
(Protein Tyrosine Phosphate Non-Receptor Type 22) has pathway, by forming a bipartite transcription factor 42. The
recently been connected to a putative T1D gene 39, 40. genes and gene functions related to diabetes are shown in
Additionally, T1 diabetes mellitus and cytotoxic T- Table 1.
lymphocyte associated protein-4 (CTLA-4) may be

Table 1 Diabetes Gene and its Functions.

Gene Gene name Gene Function Type of Diabetes
HLA Human leukocyte Antigen Immune System Regulation T1D
Involved in numerous aspects
INS Insulin T1D
of metabolism
CTLA44 Cytotoxic- T-lymphocyte associated protein 4 Immune System Regulation T1D
PTPN22 Protein Tyrosine Phosphate, non-receptor Type 22 Immune System Regulation T1D
ATP Binding Cassette subfamily C, sulfonylurea Regulation of potassium
ABCC8 T2D
receptor channels and insulin release
CAPN10 Calpain 10 Protease T2D
Control hepatic glucose
GCGR Glucagon Receptor production and insulin T2D
secretion
GCK Glucokinase Glucose metabolism T2D
Potassium inwardly rectifying channel subfamily J,
KCNJ11 Regulation of insulin secretion T2D
member 11
PPARG Peroxisome proliferator-activated receptor- γ Transcription Factor T2D
HNF4FA Hepatocyte Nuclear Factor 4α Transcription Factor T2D
SLC2A1 Glut 1 Glucose transporter T2D

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 Comorbidities Associated with Diabetes Mellitus various comorbidities along with diabetes such as POSTN
Individuals diagnosed with diabetes mellitus are at a and TCF7L2 13,42.
significant risk for a number of related problems and
comorbidities, which can be brought on by particular drugs, The most prevalent co-occurring diseases, according to
environmental conditions, or hereditary factors. Merck and Co. researchers, were hypertension, obesity or
Hypoglycemia, pancreatitis, liver disease, cardiovascular overweight, hyperlipidemia, chronic renal disease, and
disease, congestive heart failure, chronic kidney disease, cardiovascular disease. Researchers found that hypertension
genital mycotic infections, neuropathy, retinopathy, urinary and hyperlipidemia were the most common comorbid co-
tract infections, hyperlipidemia, and overweight/obesity are conditions. These were followed by overweight or obesity
among the common comorbidities that are common in the and hypertension, overweight or obesity and hyperlipidemia,
T2DM patient population 43. Cardio-vascular diseases and hypertension and chronic kidney disease (CKD),
diabetes generally act as comorbidities in some patients. hyperlipidemia and cardiovascular disease (CVD), and
Certain macrovascular and microvascular complications overweight or obesity and CVD.. The data from the research
result from T1DM. Genes are also altered or affected to cause is shown in Figure 6.

Fig 6 Comorbid Conditions in Diabetic Patients.

 Microvascular Complications amputation is mostly caused by diabetic peripheral

Microvascular complications are nephropathy, neuropathy, which affects about 70% of people with
retinopathy, and neuropathy are shown in Figure 7. Each year, diabetes44. Peripheral neuropathy's pathogenesis is unknown,
around (12,000 - 24,000) new cases of eye-related problems however it is believed to be related to inflammation,
follow like loss of vision caused by diabetic retinopathy 44. decreased blood flow, and nerve demyelination. It is also
Within five years of diagnosis, diabetic retinopathy had recognized that oxidative stress, lipid abnormalities, elevated
manifested in 14% of type 1 and 33% of type 2 diabetes polyol flux, and advanced glycosylation end products are
patients in the Wisconsin Epidemiologic Study of Diabetic metabolic abnormalities caused by chronic hyperglycemia
Retinopathy (WESDR) 45. Diabetes-related tissue damage has that might result in peripheral neuropathy. Since exposure to
been linked to anomalies in the hexosamine, polyol, and hyperglycemia appears to be the most significant risk
protein kinase C pathways that are brought on by covariate, strict glycemic management is recommended to
hyperglycemia 46–48. Up to 40% of diabetic patients develop stabilize and occasionally improve symptoms48. Some of the
diabetic nephropathy, and hypertension increases the risk of findings suggested that several genetic factors/ candidate
this microvascular disease 49,50. On a histopathologic level, genes are responsible for enhancing the risk of diabetes
diabetic nephropathy is distinct from other causes of renal nephropathy complications - Adiponectin, IGF-1, IGF-
disease. The mesangial matrix first rises, then the glomerular binding protein 1, TGF-β receptor, Collagen type, Laminin,
basement membrane, which in some cases may proceed to Tissue inhibitor of metalloproteinase, Carnosinase,
more severe diffuse or nodular glomerulosclerosis 50. Foot Neuropilin 1, Aquaporin 1.61.

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Fig 7 Complications of Diabetes.

 Macrovascular Complications sustaining procedures. Furthermore, likened to nations with a

Diabetes raises a person's risk of CVD and stroke by two inferior incidence of diabetes, those with a high pervasiveness
to four times (44) as compared to non-diabetics. The Multiple of diabetes recounted higher numbers of COVID-19
Risk Factor Intervention Trial (MRFIT) found that even after infections and fatalities. During the pandemic, hospitalization
accounting for age and other CVD risk factors like smoking, rates for COVID-19-positive diabetic patients were 1.7 times
hypertension, and hypercholesterolemia, patients with higher than for non-diabetic patients. According to IDF Atlas
diabetes still had a higher likelihood of having a CVD. 2021, the risk of death for diabetics hospitalized with
Cardiovascular disease (CVD) is much more common in COVID-19 is estimated to be 2.3 times higher than for non-
people with type 1 and type 2 diabetes, and the risk is diabetics admitted to the same hospital or healthcare system.
increased when additional risk factors are present (49). It is expected that if diabetes becomes more common, there
will be a greater need for rehabilitation treatments to mitigate
 Covid 19, Rehabilitation and Diabetes any negative effects the illness may have (3). A thorough,
The World Health Organization (WHO) declared the lifelong treatment plan is necessary for diabetes management
(COVID-19) pandemic SARS-CoV-2 a global health in order to meet predetermined objectives. Achieving
emergency in March 2020. The pandemic has had a severe glycemic control, enhancing quality of life, averting or
detrimental influence on healthcare systems, the global delaying complications, and educating patients about their
economy, and our way of life. Acute respiratory distress illness are the primary objectives of diabetes rehabilitation. It
syndrome (ARDS), COVID-19 pneumonia, and respiratory is well recognized that physical activity lowers intra-
failure are among the catastrophic consequences of COVID- abdominal fat, a known risk factor for insulin resistance,
19 infection that preliminary research suggested were more improves insulin sensitivity to high blood glucose, and
likely in people with diabetes. These exploratory prevents cardiovascular problems. This is because more
investigations demonstrated that, as compared to individuals blood flowing to the muscles causes the muscles' cells to
without diabetes, those with diabetes required more absorb more glucose (1,2).
mechanical ventilation, hospitalization, and other life-

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