Diabetes mellitus: genetics and associated diseases.

How do clinicians recognize diabetes mellitus? We recognize it as the inability of the body’s metabolic processes to maintain a blood sugar within a normal limit commensurate with the maintenance of vascular, neurological health and the ability to maintain immunity and prevent degenerative changes which lead to an early death. Vascular health enables us to maintain a normal blood pressure, good blood flow through the cardiac and cerebral blood vessels and normal configuration of the glomerular capillaries and adequate peripheral blood supply. Neurological health appears to be dependant on prevention of abnormal metabolites like inisotol etc from being deposited in the myelin sheath causing somatic and autonomic neuropathy with resultant dysfunction. The high blood sugar in the tissues results in easy proliferation of pathogens which our immune system may not be able to fight and also there is delayed healing.

How do we confirm our suspicion of diabetes as a diagnosis? We measure the blood sugar level and compare it to a level accepted as normal on the basis of measurement of blood sugar measurements in people without diabetes. The blood sugar may be measured in the fasting state, or two hours post-prandial or at a random time in relation to meals. It is important to know in which state the blood was drawn because the accepted normal level will be different. It is equally right to draw the blood at any time so long as the relationship to intake of food is known. We also measure the percentage of glycosylated hemoglobin in the blood.

  • Type 1 diabetes mellitus— Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to absolute insulin deficiency. This is usually due to autoimmune destruction of the beta cells (type 1A).
  • Type 1B diabetes. These are people with insulin dependent diabetes who do not have detectable antibodies.
  • Type 2 diabetes. Type 2 diabetes is by far the most common type of diabetes in adults and is characterized by hyperglycemia and variable degrees of insulin deficiency and resistance. It is a common disorder whose prevalence rises markedly with increasing degrees of obesity. Insulin resistance and insulin deficiency can arise through genetic or environmental influences, making it difficult to determine the exact cause in an individual patient.
  • Latent autoimmune diabetes in adults (LADA). 7.5 to 10 of people with apparent type 2 diabetes have antibodies to the islet cells.
  • New classification of diabetes based on beta cell autoimmunity, beta cell function, clinical features, and body weight. The high prevalence of
  • Classification based on overweight/obesity in the population has further complicated classification systems with an added element of insulin resistance even in type 1 diabetes. 
  • It is anticipated that other subtypes of type 1 (and type 2 diabetes) will become more clearly defined in the future such as ketosis prone type 2 diabetes.

Do you need to do antibody studies in all cases of type 1 diabetes?  

We measure autoantibodies when the diagnosis of type 1 or type 2 diabetes is uncertain by clinical presentation:

  • Thin older patient with poor response to initial therapy with sulfonylureas or metformin
  • Personal or family history of autoimmune disease
  • Overweight or obese children or adolescents presenting with apparent type 2 diabetes, who actually may have an early presentation of type 1 diabetes


How do researchers perceive diabetes mellitus? 

Diabetes comprises a heterogeneous group of diseases on two accounts;

  • the inheritance of the disease
  • the pathophysiology of the disease and it’s link with obesity.

The current  concept  or paradigm is that early beta cell dysfunction is likely to be a primary defect in the pathophysiology of diabetes, regardless of “type.” The worsening of the disease depends on progressive loss of beta cell function.

Genetics Defects in  Diabetes. Multiple genetic defects are responsible for a predilection for both type 1 and type 2 diabetes.

Type 1. The human leukocyte antigen (HLA) alleles have a large effect, followed by insulin gene polymorphisms, and PTPNN22. There are multiple other genes which may be responsible.

Type 2. Monogenic causes of type 2 diabetes represent only a small fraction of cases and commonly inherited polymorphisms individually contribute only small degrees of risk for, or protection from, diabetes. Most of the genetic risk for type 2 diabetes results from complex polygenic risk factors.

Genes may also be responsible for protection from type 2 diabetes.

Maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is a clinically heterogeneous disorder characterized by noninsulin-dependent diabetes diagnosed at a young age (<25 years) with autosomal dominant transmission and lack of autoantibodies. These patients are likely to suffer macro and micro vascular complications of diabetes.

MODY is the most common form of monogenic diabetes, accounting for 2 to 5 percent of diabetes.

Several abnormalities have been identified, each leading to a different type of disease.  The genes involved control pancreatic beta cell development, function, and regulation, and the mutations in these genes cause impaired glucose sensing and insulin secretion with minimal or no defect in insulin action. Mutations in hepatocyte nuclear factor-1-alpha (HNF1A) and the glucokinase (GCK) gene are most commonly identified, occurring in 52 to 65 and 15 to 32 percent of MODY cases, respectively. Mutations in hepatocyte nuclear factor-4-alpha (HNF4A) account for approximately 10 percent of cases. Some members of a family have the genetic defect but do not develop diabetes; the reason for this is unclear.

Hepatocyte nuclear factor-4-alpha.  Mutations in the HNF4A gene on chromosome 20 cause the condition formerly called MODY1. HNF4A is expressed both in the liver and in pancreatic beta cells. One of its functions is to regulate positively the activity of HNF1A, the affected gene in the previously labeled MODY3 syndrome.

Glucokinase gene. More than a dozen mutations in the GCK gene on chromosome 7 have been described and were formerly called MODY2. Defects in the expression of GCK, which phosphorylates glucose to glucose-6-phosphate and probably acts as a glucose sensor, result in a higher threshold for glucose stimulated insulin secretion. On occasion, the expressed enzyme functions, but is unstable, again leading to an insulin secretory deficit.

Hepatocyte nuclear factor-1-alpha — One of several mutations in the HNF1A gene on chromosome 12 was formerly called MODY3. This form of diabetes is more common among European patients

Insulin promoter factor 1 — Mutations in the insulin promoter factor 1 (IPF1) gene can lead to what was called MODY4 by reduced binding of the protein to the insulin gene promoter  and perhaps by altering fibroblast growth factor signaling in beta cells.

Hepatocyte nuclear factor-1-beta.  Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene produce a syndrome that was formerly called MODY5. Affected patients can develop a variety of manifestations in addition to early-onset diabetes. These include pancreatic atrophy (on computed tomography [CT] scan), abnormal renal development (renal dysplasia that can be detected on ultrasonography in the fetus, single or multiple renal cysts, glomerulocystic disease, oligomeganephronia [a form of renal hypoplasia]), slowly progressive renal insufficiency, hypomagnesemia, elevated serum aminotransferases, and genital abnormalities (epididymal cysts, atresia of vas deferens, and bicornuate uterus)

Neurogenic differentiation factor-1 — Mutations in the gene for neurogenic differentiation factor-1 (also called NEUROD1 or BETA2) can lead to what was called MODY6 [51,52]. NEUROD1 normally functions as a regulatory switch for endocrine pancreatic development.

Do you need to do genetic studies for all cases of diabetes?

No because at present we have no effective therapeutic intervention. Preconception studies are unlikely to help because of the multiple polymorphism. Genetic studies, however are done in patients with MODY.

Indications for genetic testing —

It is important to distinguish MODY from type 1 and type 2 diabetes because the optimal treatment and risk for diabetes complications varies with the underlying genetic defect. As an example, patients with MODY due to HNF1A or HNF4A mutations are frequently misdiagnosed as having insulin requiring type 1 diabetes because they present at an early age and are not obese. However, many of these patients can be successfully managed with sulfonylureas monotherapy. In addition, distinguishing MODY from type 1 and type 2 diabetes allows earlier identification of at-risk family members.

Wolfram syndrome.  The Wolfram or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome, originally described by Wolfram in 1938. This disorder is inherited as an autosomal recessive trait with incomplete penetrance.

Diseases of the exocrine pancreas. Diabetes is more likely to develop diabetes after disease of the pancreas or pancreatic surgery if they already have a tendency for  diabetes.   Diabetes that occurs in patients with pancreatic disease is usually insulin requiring. However, it is different from typical type 1 diabetes in that the pancreatic alpha cells, which produce glucagon, are also affected. As a result, there is an increased risk of hypoglycemia, both treatment related and spontaneous.

Other exocrine pancreatic diseases associated with diabetes are:

  • Cystic fibrosis.
  • Hereditary hemachromatosis.
  • Fibrocalculous pancreatic diabetes
  • Chronic pancreatitis.

Endocrinopathies. Several hormones, such as epinephrine, glucagon, cortisol, and growth hormone, antagonize the action of insulin. Increased release of these hormones constitutes the protective  counter regulatory response to hypoglycemia. On the other hand, primary oversecretion of these hormones can result in impaired fasting glucose or overt diabetes.

  • Cushing’s syndrome, due to pituitary or adrenal disease or to exogenous glucocorticoid administration
  • Acromegaly
  • Pheochromocytoma
  • Glucagon-secreting tumors (glucagonomas)
  • Somatostatin-secreting tumors (somatostatinomas).
  • Hyperthyroidism.

Gestational diabetes occurs when a woman’s pancreatic function is not sufficient to overcome both the insulin resistance created by the anti-insulin hormones secreted by the placenta during pregnancy (eg, estrogen, prolactin, human chorionic somatomammotropin, cortisol, and progesterone) and the increased fuel consumption necessary to provide for the growing mother and fetus. It is estimated to occur in approximately 2.1 percent of pregnant women, usually developing in the second or third trimester.

Viral infections. A large number of viruses can damage or destroy the islet cells of the pancreas including Hep C.

A large number of drugs can cause diabetes.

Several uncommon forms of immune-mediated diabetes have been identified.

Stiff-person syndrome — The stiff-person syndrome (formerly called stiff-man syndrome) is an autoimmune disorder of the central nervous system, which is characterized by progressive muscle stiffness, rigidity, and spasm involving the axial muscles, with severe impairment of ambulation. Patients usually have high titers of anti-glutamic acid decarboxylase (GAD) antibodies, and diabetes occurs in approximately one-third of cases.

Anti-insulin receptor antibodies — Anti-insulin receptor antibodies can bind to insulin receptors and either act as an agonist, leading to hypoglycemia, or block the binding of insulin and cause diabetes.

I hope now you will be able to remember that in taking the history of the symptoms, associated medical problems, a family history you will be able to determine the cause of the diabetes in a person and be able to determine when to do extensive testing and not just the blood sugar alone.








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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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