Diabetes mellitus
Classification
DM is classified as a type 1 DM and type 2 DM. however, other types of diabetes in which molecular pathogenesis is better understood and associated with a single gene defect. Type 1 DM develops due to autoimmunity against beta cells which produce insulin so there is near no insulin. Type 2 DM develops due to multiple causes by insulin resistance, impaired insulin secretion, and increased liver glucose production. Type 2 DM disease progression referred to as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).| Type of DM | Normal Glucose | Pre diabetic | Diabetes Mellitus |
| FPG | 100 mg/dl | 100-125 mg/dl | 126 mg/dl |
| 2-h PG | 140 mg/dl | 140-199 mg/dl | 200 mg/dl |
| HbA1C | <5.6 % | 5.7-6.4% | >6.5% |
Other types of DM
Other types of diabetes include specific gene defects in insulin secretion. Maturity onset diabetes of young (MODY) and Monogenic diabetes are a subtype of DM characterized by inheritance, early onset of increased blood glucose, and impaired insulin secretion. Disease like cystic fibrosis or chronic pancreatitis may damage the islet cell of the pancreas. Hormones that fight against insulin lead to DM.Gestational diabetes
Glucose tolerance developing during the second and third trimester of pregnancy is defined as gestational diabetes however detection of diabetes during 1 st trimester classified as preexisting gestational diabetes. Most women with GDM revert back to normal after delivery but have risk 35-60% of developing DM in the next 10-20 years.Incidence and distribution
The incidence of diabetes has increased in the last 2 decades, 30 million cases in 1985 to 415 million in 2017 and it will reach 642 million by the year 2040(see www.idf.org). The prevalence of DM2 is more due to obesity reduced activity as countries become more industrialized, and aging of the population. In 2015 China has 109.6 million, an India (73 million) person with diabetes although 50% of people worldwide were undiagnosed. The prevalence of DM in age >65 was 25.9% and the same prevalence in males and females. This variability is due to genetic, behavior, and environmental factors. Diabetes is a major cause of mortality, globally it responsible 5 million deaths and in 2015 673million dollars were spent on health expenditure worldwide.Diagnosis of diabetes
Symptoms of diabetes and random blood sugar >200 mg/dlFasting blood sugar >126 mg/dl
Hemoglobin A1C>6.5
2-hour blood sugar >200
Risk factors of type 2 diabetes
Family history of diabetes, BMI>25, physical inactivity, race /ethnicity, impaired fasting glucose/impaired glucose tolerance or HBA1c 5.7-6.4%, history of Gestational diabetes, high blood pressure, high cholesterol, polycystic ovarian syndrome, heart disease.Screening
Most people who match the above criteria for DM are asymptomatic and don’t know they have the disease. The study suggests that diabetes may present a decade before it appeared and some person has one of the complications at the time of diabetes. So those who have BMI>25 and age >45 needs to screen every 3 years.Regulation of glucose
Overall regulation
Glucose regulation (sugar) depicts an energy intake from ingested food, liver glucose production, and peripheral tissue uptake and utilization. the pancreas produces insulin which is an important regulator of glucose but neural input and another hormone (glucagon) also control glucose supply and utilization.biosynthesis of insulin
beta cells of the pancreas secret insulin, initially, it has 86 amino acids. Subsequent proteolytic events lead to proinsulin it is similar to insulin and also binds to insulin receptors. Then mature insulin along with the c-peptide secret. C-peptide is an important marker for differentiating endogenous or exogenous origin of insulin.Insulin secretion
Insulin is a necessary molecule of glucose uptake act by GLUT pathway, glucose converts into pyruvate to produce ATP by mitochondria which activates APT-sensitive K+ channel resulted in depolarization of voltage-dependent ca+ channel. It will lead to increase ca+ level in the cell which resulted in secretion of insulin and c- peptide.Pathogenesis of type 1 DM
Type 1 DM is the result of genetic environmental, and immunologic factors and finally lead to autoimmune-mediated destruction and insulin deficiency. It develops at any age but most commonly before 20 years also the rate of decline of beta-cell functions differently individually. There are many stages in the development of disease first genetic and environment leads to the destruction of beta-cell then stage 1 and stage 2 stage (overt diabetes. It develops symptoms when 80% of the cell died. At some point there is no need for insulin but after that patient becomes without insulin. It is a research topic whether we can regenerate this beta-cell by any methods?Genetic consideration
Type 1 DM involves multiple genes, the major susceptibility gene is located in the HLA region of chromosome 6 which is accountable for 40-50% of genetic risk of developing DM type 1.this region also contain MHC (major histocompatibility complex), which present antigen to T lymphocytes thus involved in the immune response. Both associated genes were found which protect as well as contribute to type 1 DM.Pathophysiology
Although other islet cells are functionally similar to insulin and beta-cell they are somewhat spared so it arise a question of why it so happened. By finding these answers researchers are found an abnormality in hormonal and cellular arms of immunity.1) islet cell antibody. 2) Activated lymphocytes in islet 3) T lymphocytes proliferate when it stimulated by islet protein.4) release cytokine within insulitis.Immunological markers
Islet cell antibodies (ICA) are units of different pancreatic cell antibodies such as GAD, insulin, IA-2/ICA-512, and ZnT-8 serve as a marker for the autoimmune process. ICA present in 85% individual of type 1 DM.Environmental factors
It is very difficult to identify the triggers but virus, bovine milk protein, nitrosourea, vitamin D deficiency, and environmental toxin.Prevention of Type 1 DM
We have tried many aspects like insulin to prevent type one DM but did not prevent however it is a research topic for further preventing autoimmune origin of type 1 DM.Type 2 diabetes mellitus
Insulin resistance and abnormal insulin secretion are the main causes to develop DM type 2. Most of our current understanding of DM type 2 pathophysiology and genetic origin are different in the ethnic population.Genetic consideration
Type 2 DM has strong genetic susceptibility. If both parents who have DM have increased chances of DM 40% to their child. In addition, environmental factors like obesity, poor nutrition, and physical inactivity are contributory factors. Gestational DM has an increased risk to develop DM in the child. Transcription factors 7-like gene have been associated with type 2 DM. genetic polymorphisms also found in the gene encoding peroxismal proliferator activator receptor y, inward rectifying potassium channel, zink transporter, IRS, and calpain.Pathophysiology
Type 2 DM is characterized by impaired insulin secretion, insulin resistance, and excessive glucose production by the liver, abnormal fat metabolism, and systemic low-grade inflammation. Obesity visceral or central evidenced by the hip to waist ratio (>80% of parents are obese). Insulin resistance leads to more insulin secretion by the beta-cell over the period it cannot tolerate higher insulin consequence into further beta cell destruction and increased production glucose by the liver, characteristic of overt DM.Metabolic abnormality
Abnormal muscle and fat metabolism
Insulin resistance decreased the ability of insulin to get on to the tissue. More insulin resistance leads to obesity. Increase fasting plasma glucose caused by increase production by the liver and increase glucose after meal caused by decrease peripheral conversion. Precise molecular mechanism not known but insulin receptor and its phosphorylation and de-phosphorylation defect is thought to be the main cause of insulin resistance. Lipid deposition in the muscle leads to impairment in the ATP production and generate lipid peroxides. Hyperinsulinemia may lead to atherosclerosis.Obesity accompanying type two DM particularly central or visceral. Brown fat has a thermogenic capacity. Increase adipocytes lead to high free fatty acids other cell products. It secret biologic product nonesterified free fatty acid, retinol-binding protein 4, leptin, TNF, resistin, IL-6.inaddition regulating appetite and body weight it sensitized insulin.
see also my blog on obesity
Impaired insulin secretion
Insulin secretion and sensitivity are inter-related. Initially, mild insulin secretion defect leads to increase glucose in the blood it stimulates further insulin release. The other non-glucose secretagogues like arginine are preserved but beta cell destruction is going on. Decrease secretion of insulin is thought to be by a second gene defect. Islet amylin deposition leads to fibrosis and lipotoxicity occurred and impaired its function.Increase hepatic glucose and lipid production
Due to increase insulin resistance high insulin in the body, in the presence of high insulin it fails to suppressed glucose production so it manifested as fasting hyperglycemia and decrease glycogen storage. Due to insulin resistance lipid comes out from the adiposities and cleared by the liver which resulted in high VLDL very high low-density lipoprotein. And responsible for dyslipidemia reduced (high-density lipoprotein) HDL and low (low-density lipoprotein) LDL.Insulin resistance syndrome
Metabolic syndrome or syndrome x includes insulin resistance, hypertension, dyslipidemia (decrease HDL and elevated triglyceride) central or visceral obesity, type 2 DM or IGT/IFG, and accelerated cardiovascular disease.Acanthosis Nigerian signs of hyperandrogenism (hirsutism, acne, oligomenorrhea in female
Type A: young women with obesity and feature of hyper androgenism.
Type B: middle age women hyper androgenism and auto immune disease
Polycystic ovary syndrome (PCOD) affect in pre-menopausal women characterized by anovulation and hyperandrogenism.
Lipodystrophy characterized by selective lipid tissue destruction may be inheritance or variable.
Prevention
Type 2 DM can be prevented by lifestyle modification and pharmacological agents. Those who pre-diabetic should reduce their weight and diet and increase physical activity as well as screen for heart disease. Diabetes prevention program (DPP)demonstrated intensive changes in lifestyle like diet and exercise for 30 minutes /day five times /every week delay development of DM by 58%.those who have a Family history of DM should be maintained BMI in a normal range. Many drugs also delay disease onset but yet not FDA approved
Dr Manish Khokhar
Works Cited
Jameson, J. Larry, et al. Harrison's Manual of Medicine. McGraw-Hill, 2020.
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