Essay: Metabolism

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  • Metabolism
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Metabolism is the term used to describe biochemical proses that occur within a living organism which will either produce or consume energy in order to maintain life. The main function of metabolism is to make energy, get rid of waste products and transporting substances. Furthermore, metabolism can be divided into 3 major pathways which are catabolism, anabolism, and waste disposal. Catabolism is the breakdown of molecules to obtain energy. Anabolism is the synthesis of simple molecules into complex macromolecules. Lastly, waste disposal is a process of eliminating the toxic waste product from other pathway.

Inherited metabolic disorders are genetic conditions that result in metabolic problems. This condition occurs due to the defective of the gene causes in deficiency of the enzyme. The enzyme is either not produced by the body at all or it is produced in the form that cannot be used by the body. The absence of certain enzyme may cause in buildup of toxic chemicals or something that the body needs may not be made. The code for producing an enzyme usually original -originated?- from a pair of genes. Individuals with inherited metabolic disorders inherited two copies of defective gene from their both parents as both parents are the carrier. Apart from that, autosomal recessive inheritance is a form of genetic transmission where a child who inherits two defective gene copies which cannot produce enough effective enzyme and develops the genetic metabolic disorder.

There are a lot of metabolic disorders that have been identified, and new ones continue to be discovered. Basically, metabolic disorders are divided into 2 main categories which are small molecules diseases and organelle diseases. Small molecules diseases include amino and organic acidemias, urea cycle disorders, fatty acid oxidation defects, carbohydrate metabolism defects, mitochondrial oxidative phosphorylation disorders, purine and pyrimidine metabolism disorders and pyruvate metabolism disorders. Small molecules diseases are often presented as more acutely and many lead to acute encephalopathy as they result in a small diffusible metabolite or precursors that accumulate in the brain. Moreover, four well-defined groups of genetic diseases in man can now be recognized in which the functions of an intracellular organelle are impaired: lysosomal storage diseases, mitochondrial disorders, endoplasmic reticulum storage diseases, and peroxisomal diseases. (Gouda, A. S., 2016).


Diabetes, also known as Diabetes mellitus, is a condition where the plasma glucose concentration is raised chronically above normal levels which lead to a series of symptoms such as passing large quantities of sweet-tasting urine (Drury. P. L & Gatling. W, 2005). There are many factors leading to glucose abnormality, but the main cause is due to the lack or abnormal functioning of insulin (Bilous. R & Donnelley. R, 2010). In a healthy person, after glucose intake, insulin is required. Insulin is a hormone secreted by beta cells in the pancreatic islets of Langerhans in the liver cells to help increase glucose uptake by a process called glycogenesis. The secretion of insulin will then lower plasma glucose concentration when glucose is broken down into glycogen and stored in liver and muscle cells.

However, with diabetes, this system does not work. The two common symptoms are insulin deficiency and insulin resistance. If the pancreas cannot produce enough insulin, it is known as insulin deficiency. Besides that, insulin resistance happens when the cells of the body are resistant to the insulin and have trouble absorbing glucose. As time goes by, glucose level in the blood plasma will be elevated (hyperglycemia) and this condition will eventually develop into diabetes. There are many types of diabetes, though the most common types are Type 1 diabetes and Type 2 diabetes.

Type 1 diabetes is also known as juvenile diabetes, usually diagnosed in children and young adults. It is an autoimmune condition in which the immune system destroys beta cells in the pancreas (Daneman. D , 2006) that produce insulin. Thus, when production site of insulin is off, glucose in the body cannot be broken down and leads to high blood sugar level thus resulting in few complications as in -such as?- stroke, kidney disease, eye problem and nerve damage. It is proven that individuals with type 1 diabetes are ten times higher risk associating with cardiovascular diseases including myocardial infarction, stroke, angina, and need for coronary-artery revascularization than age-matched no-diabetic populations (Orchard et al., 2006).

In contrast, type 2 diabetes is insulin resistance where the normal insulin sensitivity is loss (Drury. P.L & Gatling. W, 2005). To be more specific, insulin cannot adequately control the use of sugar from food thus leading to sugar builds up in the blood (Vijan. S, 2010). Individuals which are older than 45 years old, with family history of type 2 diabetes and overweight are most likely to get type 2 diabetes. Over time, long term complications will be developed as in problems in kidneys, eyes, heart and nerves.

Aside from type 1 and type 2 diabetes, gestational diabetes is common during pregnancy and higher risk in pregnant women with obesity. Women diagnosed with gestational diabetes are most likely at risk for type 2 diabetes after giving birth. Gestational diabetes will affect both maternal and offspring. Maternal with gestational diabetes tends to give birth to large size baby and thus leading to difficulties during delivery. Besides that, it will also increase risk for preeclampsia and maternal death. On the other hand, offspring will be associated to stillbirth and abortion.

There are other types of diabetes, for instance monogenic diabetes and cystic fibrosis-related diabetes. Monogenic diabetes is a form of disease that inherited dominantly or recessively due to mutation in single gene (Hattersley, 2009). Cystic fibrosis-related diabetes is common in people with cystic fibrosis and they have both type 1 and type 2 diabetes symptom which are loss of islet beta cell mass and insulin deficiency (Zirbes. J & Milla. C. E, 2009).


Lack or absence of the insulin production in the body cause the glucose level to rise. This condition might affect other metabolic pathway such as lipid break down and protein break down as well. There are two types of diabetes, which are the type I and type II diabetes.

Type 1 diabetes mellitus is due to the autoimmune injury to the beta cells of the Islet of Langerhans in the pancreas where the beta cells were attacked by the body’s own immune system which cause a failure in insulin production. While type II diabetes is due to insulin resistance, in which the insulin produced by the body cannot be used properly by the cells due to a damage in the insulin-binding proteins’ receptor. (repeated) Glucose is a type of carbohydrates and it involves in four types of inter-related metabolic pathway which are glycolysis, gluconeogenesis, glycogenolysis and glycogenesis. While insulin is an enzyme in our body which plays an important role in regulating the level of glucose in our body. Since there is a lack in insulin in Type I diabetic patient and ineffective usage of insulin in Type II diabetic patient, the uptake of glucose from the blood will be lesser and this causes their body to use other energy sources such as lipids and proteins.

Low insulin level will cause an increased level of cAMP. Most of the metabolic pathway in our body are being balanced by the level of glucagon and epinephrine on one hand and by insulin on the other hand. In a normal person, both glucagon and epinephrine will activate adenylate cyclase and form cAMP. Meanwhile, insulin will produce phosphodiesterase which will the cleaves cAMP. In a diabetic patient, the level of insulin is very low, and this condition will cause the level of cAMP to increa
se, thus activating protein kinase A (PKA). cAMP and PKA will control the level of a bifunctional enzyme which is phosphofructokinase-2 and fructose-2,6-biphosphotase in glycolysis. So, when the level of cAMP and PKA is high, the enzyme will be phosphorylated and cause bisphosphatase to be activated. The activation of bisphosphatase will then cause the level of fructose-2,6-bisphosphatase to be lowered. Thus, glycolysis will be inhibited and gluconeogenesis is activated. Excess amount of cAMP will also cause glycogen synthesis to be inhibited and the break down of glycogen increases. When both gluconeogenesis and glycogen break down are activated in the liver, accumulation of excess glucose will occur.

In a diabetic patient, the lack of insulin in their body causes lipids and protein break down as well. In term of lipid break down, the high level of PKA and cAMP causes lipase to be activated and the break down of triacylglycerol occur. Free fatty acids and glycerol are produced from the break down process and they are released to the bloodstream. Glycerol will then undergo gluconeogenesis process while the fatty acids will undergo ketogenesis process. Both of these processes occur in the liver.

In term of protein degradation, amino acids from the break down of protein will be degraded. Amino acids will be converted to keto acids and enter TCA cycle as an intermediate. From the TCA cycle, malate will then be converted to become pyruvate and the pyruvate is then transaminated to become alanine. Alanine will then enter the liver and undergo gluconeogenesis. Thus, more glucose will be produced.


Clinical symptoms of diabetes can help in early detection. There are 3 classic symptoms encountered by diabetic patients which are excessive thirst, polyuria and weight loss. Excessive thirst in diabetic patients also known as polydipsia is due to dehydration as excess fluid is lost in the urine as well as salt and other electrolytes. The acute thirst in Type 1 diabetes may be almost unquenchable. Some might crave for sugar-containing fluid such as coca-cola to quench their thirst which make the situation worse.

Polyuria is a condition of excessive urine output from our body. Polyuria develops when the rate of glucose enters the proximal tubules of kidney exceeds the capacity of kidney to return glucose into the bloodstream. At this point, it is known as the renal threshold for glucose. Glucose spills over the urine as not all glucose can be reabsorbed into the blood circulation. The excess glucose in the urine causes more water to be drawn out into the urine due to osmotic effect. This leads to increase volume of urine in diabetic patients.

Weight lost in diabetic patients is due to body unable to get sufficient amount of glucose. Insufficient insulin prevent body cells from getting glucose from blood to use as energy source. This promotes glucose production by the liver where fats and protein are used as an alternative source for energy. Breakdown of fats and protein cause an overall reduction in diabetic patients’ body weight.

Besides the 3 classic symptoms mentioned above, diabetic patients may also experience other symptoms. Tiredness and lack of energy are common symptoms but not at all specific for diabetes. Blurry vision in diabetic patients is due to osmotic changes in the lens of eyes. However, blurry vision can be reduced once glucose abnormality has been corrected.

Although most diabetic patients will experienced the symptoms above, but these symptoms might not be mentioned when they develop slowly and over a long time of period. Early detection in diabetes is important as it can reduce the risk of developing complications of diabetes.


Type 1 diabetes is usually caused by the genetic factors especially the genes in the human major histocompatibility complex (MHC). It is known as immune-mediated diabetes because it has strong human leukocyte antigen (HLA) associations related to the DQA and DQB genes. It can be influenced by the DRB genes and the alleles for both HLA-DR/DQ can be either predisposing or protective. The HLA gene complex is located on the p arm of chromosome 6. IDDM1 is the HLA class II gene which has about 40-50% of the heritable risk for type 1 diabetes (Hirschhorn et al., 2003). The DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 genes are the most associated type 1 diabetes in Caucasian populations once they are evaluated as haplotypes. They have the disequilibrium linkage with DRB1*03 and DRB1*04. Those with two high-risk DRB1-DQA1-DQB1 haplotypes would have a higher risk of type 1 diabetes than those with no high-risk haplotypes. (Nejentsev et al., 1997; Lie et al., 1999)

Type 2 diabetes is caused by several factors and the gene risk has fewer genes of major effect if compared to type 1 diabetes. PPARγ, KCNJ11, and CAPN10 are the common genes that contributed to type 2 diabetes. PPARγ, peroxisome proliferator-activated receptor-γ is located on the p arm of chromosome 3. Pro allele is one of the forms of PPARγ gene lowers the sensitivity of insulin and thus increases the risk of type 2 diabetes. The KCNJ11 gene is known as the potassium channel, inwardly rectifying subfamily J, member 11 and it is located on the p arm of chromosome 11. It is one of the parts of ATP-sensitive potassium channel which regulates the release of hormones, for example, insulin and glucagon. Mutation will interrupt the channel’s activity and secretion of insulin. CAPN10 or the calpain 10 which located on the q arm of chromosome 2 encodes for calpains, a cysteine protease which is calcium-dependent. (Cox et al., 2004). Insulin secretion will be affected by the variations in calpain 10 activity.

The defective genes of MODY are autosomal dominant inherited. The HNF1A gene as the hepatocyte nuclear factor is expressed in liver and pancreas. It is the most common form of _____where mutations occur on chromosome 12 at the q arm. It is followed by the GCK gene where mutations occur on the p arm of chromosome 7. The mutation of GCK gene will produce defective glucokinase molecules which are important in the conversion of glucose to glucose-6-phosphate so that insulin secretion is stimulated by β-cell. HNF4A, IPF1, HNF1B, NEUROD1 are the less common forms of ___ caused by mutations.


Diabetes Mellitus has no cure, it can only be treated to prevent further worsening condition and controlled. The main goal of the treatment of Diabetes is to keep the blood glucose level as near to the normal range as possible. Controlling the glycaemia strictly aids in reducing microvascular and macrovascular effect associated with diabetes.

Pharmacologic treatment can be one of the effective way to treat diabetes mellitus. The identification of patient whether is insulin deficient, insulin resistant or both are the major factor to consider in this therapy. Basically, the pharmacologic treatment can be categorized into insulin therapy and noninsulin therapy.

Insulin is the first treatment and most effective method for Diabetes as it reduces hyperglycaemia. Patient who is taking insulin should monitor blood glucose frequently for instance three or more times per day. Adjustment of food intake depend in real-time blood glucose values and medical therapy ought to be educated and understand by patient. Basal-bolus therapy or insulin pump are available for patients of type 1 DM as they need insulin therapy.

A combination of insufficient insulin secretion together with resistance to insulin action can briefly explain the characteristic of Type 2 Diabetes. It needs therapy intensification with time as it is a progressive disease. Noninsulin therapy such as insulin sensitizer and incretins-based therapy are recommended to take early.

Insulin sensitizers drug such as biguanides (metformin) and thiazolidinediones have a positive a
nd durable effect in treatment of diabetes. Insulin sensitizers reduce glycemic load in body especially improving insulin action in peripheral tissues. Biguanine dosing typically twice or three time per day with starting dose 500mg/day and maximum dose of 2550mg/day. Biguanine leads to weight loss and decrease plasma triglycerides concentration by 10% to 20%. (Bailey CJ,1996). Besides, thiazolidinediones help in lower fasting and postprandial blood glucose levels. The recommended dose for thiazolidenediones is once per day with starting dose 4mg/day and maximum dose 8mg/day (Nathan DM, 2002).

Furthermore, a diabetic patient who fail to produce incretin hormone by gastrointestinal tract as secretin response to incoming nutrient and contribute to glucose homeostasis. Incretin-based therapy can help in diabetic patient to regulate glucose level as it is an effective glucose-lowering drugs. Incretin-based therapy is available as injection (GLP-1 analogs) or oral formulation (DPP-4 inhibitors). Subcutaneous injection of GPL-1 dosing is twice daily with starting dose 5 microgram. 10 microgram is titrated if starting dose is tolerated (Fonseca VA, 2008). DPP-4 inhibitors effective in lowering blood glucose levels and help reduce appetite. The dosage of DPP-4 inhibitor is depends on agents such as sitagliptin, saxagliptin, linangliptin and alogliptin. These agents are indicated for use as monotherapy or -are the indicator of?- in combination with other agents such as metformin, sulfonylureas, thiazolidinediones or insulin (American Diabetes Asocciation, 2015).

Type 1 diabetes is managed with insulin as well as dietary changes and exercise. Whereas Type 2 diabetes may can be managed with non-insulin medications, insulin, weight reduction and diatary changes. (Robert. F, Melissa CS, 2016)


Since Type I and Type II diabetes belong to one of the diseases that are most common in Malaysia, it is important for us to know how these two diseases can be diagnosed. This is essential as those people who already be identified as the diabetic patient can receive treatment early before those symptoms getting deteriorated (Sondra O’Callaghan, 2017). A few screening tests are available to diagnose diabetes and each of these tools have different abilities to predict diabetes. There are several risk factors that these screening tools take into accounts such as body mass index, age, family history, waist circumference, exercise level, dietary habits and other (Gina Agarwal, 2005).

According to American Diabetes Association, Haemoglobin A1C is a test commonly used in the diagnosis of diabetes. This test does not only identifies those people with diabetes mellitus but also act as the screening tool for those with a higher risk of developing diabetes mellitus in future. People with higher risk of developing diabetes mellitus will have a laboratory level of Haemoglobin A1C between 6.0% to <6.5% which is considered as normal range but is below critical point for diabetes. However, by having AIC level between 5.5% to 6.0%, it is appropriate to conduct the preventive intervention. In the same time, people having value falls in the region between 5.7%-6.4% have the higher risk of getting cardiovascular disease as well as diabetes mellitus. A1C test is less sensitive than fasting blood glucose level due to the lower cut point but is effective in predicting risk for people to develop diabetes mellitus in the future life (American Diabetes Association, 2010).

Fasting glucose level is another test which can usually be used in the diagnosis of diabetes mellitus. Glucose level falls in between 100mg to 125mg per dl (deciliter) or (5.6 mmol to 6.9 mmol per litre) indicates that the person may have the higher risk for getting diabetes (Silvio E. Inzucchi, 2012). However, there is another classification in which fasting blood glucose that has been diagnosed is being lowered to ≥7.0 mmol l−1 (K.G.M.M. Alberti and P.Z. Zimmet, 2004). Diagnosis of diabetes should not be according to age since diabetes can occur at any age (National Diabetes Data Group, 1979).

Oral glucose intolerance test is available for diagnosis of diabetes. This test will produce 2-h values for identification of diabetes mellitus. Impaired glucose intolerance is indicated by 2-h postload glucose level in between 140 to 199 mg/dl which is also (7.8–11.1 mmol/l). However, when the value exceeds 200mg/dl (11.1 mmol/l), diagnosis of diabetes is confirmed. Except for these tests, diagnosis of diabetes can also be done through observation of symptoms with normal blood glucose concentration exceed 200mg/dl (11.1 mmol/l). This plasma glucose concentration means that measurement of glucose concentration -is ___-regardless of fasting or non-fasting state (American Diabetes Association, 2004). Diagnosis of diabetes is suggested for those who are 45 years old and above as these people are at higher risk. Diagnosis should also be conducted in every 3 years even though in the healthy person with lower risk factors (Mayfield, J., 1998).


In conclusion, carbohydrate disorders are considered as one of the metabolic disorders. One of the carbohydrate metabolic disorder is diabetes mellitus. There are type -1-diabetes, type-2-diabetes, gestational diabetes and maturity-onset diabetes of the young. It is due to the defective of certain gene and mostly affect in the production or amount of insulin. There are some classical symptoms such as polyuria, which is frequent urination, polydipsia, which is increased thirst and polyphagia, which is increased hunger. Furthermore, a few screening tests such as Haemoglobin A1C, fasting glucose level test and oral glucose intolerance test are available to diagnose diabetes. If the person has diabetes mellitus, their condition can be treated to prevent worsening condition and controlled. However, it cannot be cured Maintaining the blood glucose level near to the normal range is the main goal of the diabetes mellitus patient. They may undergo pharmacologic treatment and taking insulin sensitizers drug in order to treat and control the disorder.

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