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Inherited Diseases affecting Diabetic Patients

Inherited Diseases that affect the Diabetic Patients webinar was conducted in association with the IMA Medical Students Network- Jubilee Unit, Synerton Unit ( Amala Institute of Medical Sciences) and JournoMed. The event was held on 28th October 2022. 

Dr N Subapriya, a Senior Consultant Diabetologist from Sri Narayana Hospital and Research Centre spoke about the “Inherited Diseases that affect the Diabetic Patients.”

Diabetes compromises a group of common metabolic disorders that share the phenotype of hyperglycemia. It is a metabolic disease in which the body’s inability to produce any or enough insulin cases elevated levels of glucose in the blood. So, there are several distinct types of diabetes melitus that exist and are caused by 

  • Complexion interaction of Genetics
  • Environmental Factors
  • Lifestyle Choices 

Based on the aetiology of diabetes, factors contributing to hyperglycemia can occur. It may include reduced insulin secretion, decreased glucose utilization and an increased glucose production. So, the metabolic dysregulation associated with diabetic process is certainly caused by the change in the physiological process. It alters multiple organ systems at the first, bringing a tremendous challenge to the individual diabetic healthcare professionals. So, among individuals Diabetes Mellitus is the leading cause of any disease and it is observed among non- traumatic patients and others world wide. It also serves as a leading cause of morbidity and mortality showcasing vital features. 

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Types of Diabetes

  1. Type 1A Diabetes
    Type 1B Diabetes

2. Type 2 Diabetes is a specific type of Diabetes 

  • Genetic defects of beta cell functions
  • Genetic defects in Insulin Action 
  • Pancreatic Diabetes
  • Endocrinopathies
  • Drugs/ Chemical Induced 
  • Infections 
  • Immune mediated Diabetes
  • Genetic syndromes associated with Diabetes 
  1. Gestational Diabetes
  2. Pre Diabetes

Type 1A Diabetes results from auto-immune beta cell destruction which leads to insulin deficiency. The individuals with type 1 A diabetes lack immunologic markers. They serve as an indicator for auto immune destructive process. The beta cells gets secreted in the pancreas. However, they develop insulin deficiency with the unknown mechanism and both are prone to ketone synthesis. Selectively few patients with type 1 diabetes are even in type 1 with the idiopathic category. So, many individuals either Africans, Americans or Asians in heritage suffer from type 1A Diabetes. 

Type 2 Diabetes is a heterogenous group of disorders characterized by variable decrease of insulin resistance. This impacts insulin secretion and increases glucose production and thus creates a genetic and metabolic effects in insulin activity. This action is prominent in hyperglycemia. The type 2 diabetes is preceded by the period of abnormal glucose. It was termed as “Homeostasis.” The classified type 2 diabetes is again divided into impact fasting glucose or impact glucose tolerance of diabetes and they are main features of the current tolerance of diabetes. The term insulin dependent diabetes mellitus and non-insulin diabetes mellitus is also been discussed. Since, many individuals are with type 2 diabetes. Eventually the replier trips insulin, so, the control of glycemia. The use of the term non-insulin dependent diabetes mellitus, generate a considerable differences. Here the age doesn’t serve as the criteria in the classification of the system. Also, type 1 diabetes develops before the age of 30 years and autosomal beta cell immune destructive processes develops at any age. It is estimated that 5-10% of individuals would develop diabetes after the age they would develop type 1 diabetes. Likewise type 2 diabetes are more typically developed with increasing age. It also occurs in children being obese and adolscent. 

Pancreatic diabetes results from a pancreatic exocrine disease. The majority of the pancreatic islets are destroyed during this process. More than 80% of the pancreas is destroyed leading to exocrine pancreatic diabetes. In some cases, pancreatitis, pancreatectomy, hysterectomy, fibrosis, neoplasia, retro calculus pancreatectomy are the additional conditions observed. 

Endocrinopathies are the hormones that categorize the action of Insulin friendly to diabetes. This diabetes is a future of endocrinopathy. Example: Acromegaly and cushing’s syndrome. 

Drug Induced or Chemical Induced Diabetes and few uncommon forms of diabetes, and are immune- mediated diabetes. The aetiology of diabetes includes specific genetic types of insulin secretions in action. The metabolic impact increases the insulin secretions and brings mitochondrial abnormalities post the condition. It also impacts glucose tolerance. The maturity onset for diabetics is young. The sub type of diabetic inheritance characterized by autosomal dominant diabetes. The early onset of hyperglycemia impacts the insulin secretion. So, the mutations in insulin intake results in rare diseases which are characterized by insulin. 

Even there is a development of glucose tolerance during the pregnancy. 

Type 1 Diabetes 

Type 1 Diabetes also known as Juvenile Diabetes. Usually diagnosed in children and young adults. When the body’s own immune system destroys the insulin producing cells of the pancreas. The own immune system destroys the insulin producing self system i.e. the beta cells which produce insulin. Only 5% of the people possess this diabetes. The body doesn’t produce insulin at this stage. It is not preventable and has no primary intervention. The causes remain unknown. The predisposition to diabetes, genetics and some thing ( i.e., weather or virus etc) in the environment may triggers the disease. 

  • Type 1 A diabetes- an autoimmune beta cell destruction. 
  • Type 1 B diabetes- Immune mediator. 
  • Idiopathic

Type 2 Diabetes 

The most common form of diabetes in about 90% of cases. Used to be called on adult onset, non-insulin dependent diabetes. The body produces insulin but doesn’t use it properly. The glucose doesn’t move into cells, they pile up in the bloodstream. 

Genetic Defects of Beta Cell Function

  • Hepatocyte nuclear transcription factor ( HNF) ( Mody 1)
  • Glucokinase ( Mody 2)
  • HNF 1a ( Mody 3)
  • Insulin Promoter Factor ( Mody 4) 
  • HNF-1 ( Mody 5)
  • Neuro D1 ( Mody 6) 
  • Mitochondrial DNA

Genetic Defects in Insulin Action

    • Type A Insulin resistance
    • Leprechaunism 
    • Rabson Mendenhall Syndrome
    • Lipodystrophy Syndrome 

Genetic Syndromes associated with Diabetes 

  • Down’s syndrome 
  • Klinefilter’s syndrome
  • Turner’s syndrome
  • Wolfram’s syndrome
  • Friedreich’s ataxia
  • Huntington’s chorea
  • Laurence Moon Biedl syndrome
  • Myotonic dystrophy
  • Porphyria
  • Prader Willi Syndrome

Gestational Diabetes Mellitus ( GDM)

Having diabetes condition during the pregnancy is termed as “Gestational Diabetes Mellitus.” Few women may possess a family history of diabetes mellitus. It also occurs due to over weight or prior to pregnancy. Having gestational diabetes puts an individual at risk for having even diabetes type 2. Giving birth to a baby +9 lbs weight also puts women at risk for type 2 diabetes. 18 out of every 100 pregnant females will develop gestational diabetes mellitus ( GDM) during their pregnancy. 

Pre-diabetes

A condition in which blood sugar level is high but not enough to be type 2 diabetes. It gives an impaired glucose tolerance. Without intervention, it is likely to become type 2 diabetes within 10 years. 

Diabetes Prevention Program 

  • Lifestyle intervention group vs medicated group with metformin vs placebo group is determined. 
  • 3,243 participants were overweight and had prediabetes issues
  • Lifestyle interventions reduce diabetes by 58%
  • Metformin usage reduce diabetes by 31%
  • Diabetes Mellitus effective in both men and women among the age groups 25-44 years and the body mass index (BMI) of 30+ years

Summary: Type 2 diabetes can be prevented/ delayed with activity ( exercise) and diet. 

Symptoms

Common symptoms of diabetes include:

  • Excessive thirst and appetite
  • Increased urination ( some times as often as every hour)
  • Unusual weight loss or gain 
  • Fatigue
  • Nausea perhaps vomiting 
  • Blurred vision 
  • In women, frequent vaginal infections
  • In men and women, yeast infections
  • Dry mouth 
  • Slow healing sores or cuts
  • Itching skin especially in the grion or vaginal area 

Role of Insulin 

Once a large number of islet cells are destroyed, the body will produce little or no insulin. Insulin is a hormone that comes from a gland behind and below the stomach ( pancreas). The pancreas puts insulin into the bloodstream. Insulin travels through the body, allowing sugar entry into the cells. Insulin lowers the amount of sugars in the bloodstream. As the blood sugar level drops, the pancreas puts less insulin into the bloodstream. 

Role of Glucose 

Glucose is a sugar. It is the main source of the energy for the cells that make up muscles and the other tissues. Glucose comes from other two major sources. Food and the liver. Sugar is absorbed into the bloodstream, where it enters the cells with the help of insulin. The liver stores glucose in the form of glycogen. When glucose levels are low, such as when the individual haven’t eaten in a while, the liver breaks down the stored glycogen into glucose. This keeps glucose levels within a typical range. In type 1 diabetes, there is no insulin to let glucose into the cells. Because of this, the sugar builds up in the bloodstream. This can cause life threatening complications. 

Criteria for the diagnosis of Diabetes

  • Symptoms of diabetes plus random blood glucose concentration > 11.1 mmol/ L. ( 200 mg/ dL). 
  • Fasting plasma glucose > 7. 0 mmol/ L ( 126 mg/ dL). 
  • Two hour plasma glucose > 11.1 mmol/ L.
  • (200 mg/ dL) during an oral glucose tolerance test. 

Risk Factors 

  • Genetic Factors
  • Family Premedical History
  • Polycystic ovary syndrome condition- Irregular menses
  • Risk factors are more among races- African Americans, Hispanics and Asians > whites 
  • Age- After age 45 years, but increases in younger adults and children 
  • Environmental Factors
  • Inactivity 
  • Weight gain
  • Obesity ( BMI >25 kg/ M2)
  • History of GDM
  • Previously identified IFG/ IGT
  • History of vascular disease

Genetically Defined Monogenic Forms of Diabetes

Mody- A rare form of diabetes which is different from both type 1 and type 2 diabetes mellitus. Caused by mutation or change in a single gene. Group of inherited disorders of non- autoimmune diabetes mellitus. 

Variants of Mody

Mody 1- Genetic defects caused by mutations in genes islet cell transcription factors or glucokinase.  

Mody 2- Glucokinase gene mutation. 

Homozygous mutations in glucokinase cause severe neonatal diabetes. 

  • Mody 1 HNF 4a
  • Mody 3 HNF 1a
  • Mody 5 HNF 1b 

Mody 4

It is a rare variant caused by mutations in the insulin promoter factor ( IPF). Transcription factor regulates the pancreatic development and insulin gene transcription. 

Mody 6/ NeuroD1 

  • Monogenic
  • Autosomal
  • Dominant Disease
  • Results beta cell dysfunction 
  • Inadequate Insulin secretion 
  • Hyperglycemia 

Mitochondrial Diabetes 

Mitochondrial Diabetes is caused by poor functioning of insulin producing cells in pancreas or by insulin resistance as part of mitochondrial disease. 

Genetic Defects in Insulin Action 

Rare disorder characterized by severe insulin resistance. 

  • Type A Insulin Resistance
  • Leprechaunism 
  • Rabson Mendenhall Syndrome 
  • Lipodystrophy

Preventions 

Type 1:

  • Not preventable, as of right now.
  • Studies on ways to possibly prevent further destruction of the beta cells. 
  • Maintain and control sugar levels, take insulin injection.
  • Maintain Healthy lifestyle- exercise and diet.
  • Go for Islet transplantation if necessary?

Type 2: 

  • Primary: Maintain a healthy lifestyle 
  • Secondary: Check Hb A1 c, adjust diet 
  • Hb A1 c: blood sugar average over span of 3 months
  • Measure the percentage of Hemoglobin is coated with sugar
  • Nl: 4%-5.6%, pre diabetes: 5.7%-6.4% and diabetes- 6.5 %
  • Tertiary: Exercise and eat well
  • Always go for Foot examination

Preventions for Gestational Diabetes

Physical activity 

Researchers found being physically active before and after the pregnancy reduced the risk of GDM by about 70% or more. 

Diet

A study showed that each 10 gm increase in fibre a day reduced the risk of GDM by 26%. 

The Future 

Regenerating Human beta cells

Both type 1 and type 2 diabetes result from a complete or partial loss of beta cell number and function. Thus, from a therapeutic standpoint, activating the regeneration of human beta cells could prevent or even reverse the onset of diabetes. Multiple approaches to beta cell replacement have been developed including the regeneration of an individual’s own beta cells, induction of the human beta cell from stem cells, reprogramming of beta cells from other differentiated cell types, use of non-human beta cell sources ( pig or non-human primate islets) and finally expansion of human beta cells from decreased donors. Regardless of the origins, there is a clear need for more beta cells for cell replacement therapies for diabetes. 

Brown Fat Transplant may aid in Weight Loss and Diabetes Management

A study conducted by ADA funded researchers at the Joslin Diabetes Centre suggests that the brown fat transplants could help combat obesity and lower the risk of developing type 2 diabetes. In the January 2013 issue of the Journal of the Clinical Investigation, Laurie J Good year, Ph D and post doctoral fellow. Roseland J W Middelbeek MD showed that increasing brown fat via transplantation dramatically promotes weight loss and improves blood glucose control in mice- results that hope may translate to humans. 

There are at least two types of adipose ( fat) tissue. White adipose tissue is the more common type that lies below the skin, stores excess fat in the body and expands with the weight gain. Brown adipose tissue on the other hand is derived from a muscle and is highly thermogenic. In other words, it burns energy to produce heat and maintain body temperature in warm blooded organisms. Unlike, white adipose tissue, the quality of the brown fat in the body is inversely proportional to body mass index ( BMI), meaning that lean people tend to store more fat and the people who are overweight have a characterization of brown fat as “ Good fat.

Barriers to Incorporating Genes 

Identifying the Genes is the crucial factor

  • More Gene Scanning including the pooling
  • Disequilibrium based approaches
  • Human Genome Project
  • Animal Studies, all these serves as barriers in incorporating genes.

Appropriately phenotyped samples
It remains as the rate limiting step

Typing Technology 

Conclusion

Diabetes can be managed in patients as per recent scientific studies. However, diabetic management requires a lot of awareness. Healthy diet serves as a corner stone for healthy living through which the blood sugar levels can be managed. Even a proper exercise, diet plan can eliminate the diabetes to a major extent. Even the healthcare professionals have performed their research on diabetes mellitus and promoted their patient care to maximum extent i.e. towards the patients.

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