11 Draft.
Sugar and Diabetes mellitus.
PKGhatak, MD
Sugar belongs to carbohydrates and is essential for humans. Sugar is classified as monosaccharide and disaccharide. Monosaccharides are Glucose, Fructose and Galactose. Disaccharides are composed of two molecules of monosaccharides and are Sucrose, Maltose and Lactose. When disaccharides break down in the gastrointestinal tract by specific enzymes they yield the following monosaccharides.
Sucrose = Glucose + Fructose.
Maltose = Glucose + Glucose
Lactose = Glucose + Galacose.
All monosaccharides are six-carbon compounds. Fructose is the sugar of fruits and vegetables. The common source of fructose is cane sugar, table sugar, beet sugar, and soft drinks. Milk and milk products contain lactose. Maltose is a man-made disaccharide, obtained mostly from barley grain.
Glucose and fructose resemble each other both chemically; the only difference is that glucose is an aldehyde and fructose a ketone. Maltose is also an aldehyde like glucose and maltose is an Epimer of C-4 glucose. Epimer differs only in the position of the OH group of one C atom. All three monosaccharides are present as Isoforms (L & D isomers).
Carbohydrate metabolism:
The energy required for sustaining life comes from ingested carbohydrates, fat and proteins.
The breakdown of complex carbohydrates ( Cellulose, starch, and dextran) starts in the mouth by the enzyme - salivary amylase. The breakdown of carbohydrates continues in the intestine by the pancreatic amylase and various other enzymes including Lactase which splits Lactose into glucose and galactose. Many adults have Lactose intolerance due to either acquired lactase deficiency or congenital deficiency of lactase.
Glucose, fructose and galactose once formed inside the lumen of the small intestine follow their own path of metabolism. There is similarity and also different paths of the three sugars.
Glucose.
Glucose is ferried across the gut lumen into the intestinal enterocytes by the Sodium/glucose co-transporter 1 (SGLT1). SGLT1 is a member of the solute carrier family SLC 5 transporter. SGLT1 also selectively reabsorbs glucose completely from the glomerular filtrate in the proximal tubule, unless the amount of glucose in the filtrate exceeds the maximum re- absorptive capacity of SGLT, as that happens in diabetes mellitus.
Glucose utilization.
In the liver, glucose is converted into glycogen.
Glucose is taken up by all living cells by the action of Insulin. Insulin fuses with the cell membrane and create an opening for glucose molecule to enter the cell cytoplasm and then glucose molecules are taken up by the mitochondria. Glucose is used up in the tricarboxylic cycle and produces energy, generates ATPs and the end products are CO2 and H2O.
In the muscles: Some glucose is reserved in the muscles as glycogen for future use. Most of the glucose is utilized as fuel.
Hexose monophosphate shunt (HMS):
HMS is also known by other names like pentose phosphate pathways. It takes two separate paths -
1. Aerobic. This path leads to the generation of energy and NADPH (nicotinamide adenine dinucleotide phosphate). NADPH is required for the biosynthesis of fatty acids, cholesterol, and neurotransmitter.
2. Anaerobic. This path leads to the production of pentose sugars. Pentose sugars are components of Nucleic acids and nucleotides. Also through the anaerobic path, Erytrose 4 phosphate is also produced. Erytrose 4 phosphate is a component of aromatic amino acids.
Fructose:
Important dietary sources of fructose are fruits, honey, high-fructose corn syrup (soft drinks), and table sugar (sucrose). The enzyme, Sucrase breaks sucrose into glucose and fructose in the intestine.
Absorption.
GLT transporter is used for fructose absorption from the gut lumen by GLT 2 and from the enterocytes to the portal vein by GLT 5 transporter. There is no fructose in the peripheral blood or in the glomerular filtrate
Fructose utilization.
Fructose is taken up mainly by the liver and only a limited amounts by the kidneys, adipose tissues, and muscles. In the liver, fructose is converted into glycogen and all excess fructose is used in the synthesis of Triglyceride. The majority of body cells are unable to utilize fructose directly, and all the reactions involved in fructose metabolism take place outside the mitochondria. And that too is limited to the liver, adipose tissue, gut and testes.
There are two paths for Fructose utilization:
Hexokinase.
In the muscles and fatty tissue, fructose is phosphorylated by fructose-6 phosphatase and then enters the glycolysis via tricarboxylic acid cycle. Insulin is not required for fructose metabolism The majority of cells are not able to metabolize fructose.
In the Liver:
The liver turns fructose to triglyceride and triglyceride is stored in the liver cells as fat. When excess fat accumulates in hepatocytes it causes non-alcoholic fatty liver disease. The liver delivers triglyceride to fat cells of the body and an excess amount of fatty tissue produces obesity.
Relation between Fructose and insulin.
Fructose does not stimulate Insulin secretion. Glucose on the other hand stimulates insulin secretion. Insulin when reaches Hypothalamus releases the Leptin hormone. Leptin suppresses hunger. Increase fructose in the diet has no effect on hunger suppression and contributes to obesity.
The adverse effects of high triglyceride in the genesis of atherosclerosis and coronary artery disease are dealt with elsewhere in Humihealth. blogspot.com.
Galactose:
Milk sugar is lactose. In newborns and young children, lactose supplies the majority of energy requirements. Lactase split lactose into glucose and galactose. SGLT 1 transports galactose, like glycose, from the gut lumen to endothelial cells. Galactose along with glucose is taken up by the liver. Galactose is entirely utilized in the liver for the conversion into glucose by multiple enzymatic steps involving specific enzymes for those reactions. Intermediate compounds are galactose 1 phosphate and Uridine diphosphate glucose (UDP-glucose). The further enzymatic reaction produces UDP-galactose and glucose 1phosphate and by epimerization forms UDP-glucose. Several other downstream metabolic paths are involved in galactose metabolism to produce other compounds.
Synthesis of Galactose and Lactose by lactating women.
The milk glands of the breast synthesize galactose from the 3-carbon Glycerol, an intermediate product of glucose utilization. The formation of lactose takes place within the gland by the reverse action of the enzyme lactase, and the glucose molecules are obtained from the blood.
Blood sugar:
Blood sugar is Glucose, and glucose only.
It is customary to obtain blood chemistry at the annual physical examination for all adults and children in the USA. One of the routine tests is fasting blood sugar(FBS). If the FBS is 100 mg/dL or over, the result would be marked as abnormal. Based on the actual FBS, the attending physician informs the patient of the possibility of a prediabetic condition or diabetes mellitus.
FBS:
Although a fasting state is not difficult to understand and adhere to, it has many variables which may significantly alter the FBS results. When such a situation arises, the test is repeated under proper overnight fasting. That too is variable and controversial. Even then FBS is good only for that moment because blood glucose level varies from hour to hour based on food intake and physical activities. Instant blood glucose is essential for the determination of insulin dose. But glucose levels for the long term determine the long-term prognosis of diabetes mellitus. This led to the introduction of the Hemoglobin A1C blood test (HbA1C).
HbA1C test:
The reaction of Glucose with Hemoglobin:
The beta chain of the hemoglobin molecule has a terminal valine residue. Glucose molecules irreversibly bind with valine. The saturation of this N-terminal of valine with glucose is proportional to the average blood glucose level. Hemoglobin A1C is the percentage of glycated hemoglobin. Because the life of a RBC is about 120 days, the HbA1C is the sum of old RBCs and newly formed RBCs; the older RBCs have more time to combine with glucose whereas new RBCs hardly have time to be glycated. And HbC1 is a measure of the average blood glucose over 90 to 120 days. HbA1C is remarkably stable and reproducible in an individual.
False high HbA1C may result from excess hemoglobin, dehydration, frequent blood transfusion, splenectomy, or polycythemia. A low HbA1C is due to low hemoglobin level which may result from iron deficiency anemia, beta thalassemia (absent beta chain of hemoglobin), hemolytic anemia, etc
The glycation of hemoglobin involves two stages, The initial reaction is the chemical binding, then the non-enzymatic rearrangement of the molecule to a stable ketamine ( keto-amine).
Classification of Diabetes and Diagnostic Tests:
Diabetes mellitus are two distinct entities only the common link is elevated blood glucose levels.
Type I diabetes is due to a complete lack of insulin production from the Bets cells of the pancreas. The onset of the disease is early, usually in teens and generally sudden caused usually by a viral infection. Ketoacidosis and weight loss and debility are hallmarks of diabetes type I.
Type II diabetes is generally detected in middle age. It has an insidious onset and progresses slowly but steadily and produces microvascular changes in the retina, kidneys, brain and peripheral arteries. DM type II runs in the family. The blood level of insulin is usually high and insulin resistance in the tissue or structural abnormality of insulin is often demonstrated. Autoimmune diseases can manifest as diabetes by producing antibodies to insulin.
A group of diseases associated with high blood glucose levels due to various reasons other than lack of insulin or structurally abnormal insulin. These entities are Cushing's disease, chronic use of cortisone and other steroid products, pancreatitis, carcinoma of the pancreas, Liver disease, Cystic fibrosis, Polycystic disease of the ovary, stress, trauma and following severe burns, chronic use of epinephrine, use of Cyclosporine and Tacrolimus, hyperalimentation, obesity, pregnancy, poor diet habits, sedentary lifestyle and lack of physical activities.
People with high blood glucose are prone to infection but non-diabetes hyperglycemic patients do not develop ketoacidosis or progressive microvascular change unless they are prediabetic, to begin with.
Pregnancy and Blood Glucose:
Pregnancy is a risk factor for the development of Diabetes mellitus (DM). To identify the pregnant individual at risk of DM, an Oral Glucose Tolerance Test (OGTT) is performed at 24 to 28 weeks of pregnancy on a routine basis.
OGTT:
One step OGTT. A fasting blood glucose is drawn. A concentrated glucose solution of 50 gm of glucose dissolved in 250 ml of water is ingested. The patient is asked to remain sitting or remain inactive during the test. Blood samples are collected at 60 and 120 mins following ingestion of glucose.
In a modified OGTT the patient has been coached adequately and fingertip blood sugar test kits and other supplies are given to the patient and asked them to do the test at home; then mail back the blood samples by post.
In multi-step OGTT, in selected patients, the test period is 3 hrs. long and blood samples are collected at 30, 50, 90, 120. 150 and 180 minutes following oral glucose ingestion.
OGTT test is also done in very few selected Non-DM patients with an oral dose of glucose 1.75 gm / Kg body weight. Blood samples are taken at 60, 120 and 180 mins. The 3-hour OGTT is done where delayed gastric emptying or delayed pancreatic reactions to a glucose load are suspected.
Interpretation of OGTT.
|
Diagnostic Criteria of |
Fasting Glucose in mg/dL |
60 minutes post glucose dose in mg/dL |
120 minutes post glucose dose in mg/dL |
|
Normal Gestational |
Less than 90 |
130 to 140 |
Less than 120 |
|
Gestational DM |
Greater than 95 |
Grater than 140 |
Greater than 120 |
|
Normal Nonpregnant |
60 to 100 |
Less than 200 |
Less than 140 |
|
Impaired Nonpregnant |
100 to 125 |
|
140 to 200 |
|
DM nonpregnant |
100 to 126 |
|
More than 200 |
Diagnostic Tests for Diabetes Mellitus:
Diabetes Type I.
In an infant, child, or teenager, low or high blood glucose should not be dismissed. A proper evaluation requires a repeat FBS or an OGT Test in selected cases. Blood insulin level is a preferred test when a young individual develops ketoacidosis or unusual loss of weight and exhibits low energy levels.
Diabetes Type II.
For adults suspected of having DM, an 8-hour fasting glucose is the initial test. If FBS is above 100 mg/dL then the next test is the HbA1C test. Fasting is not necessary for the HbA1C test.
HbA1C criteria for normal, prediabetes and DM are as follows:
Normal or negative for DM –> HbA1c is 5.5 or less.
Prediabetic –> HbA1C is between 5.6 to 6.9
Diabetes mellitus-> HbA1C is 7 or over 7.
Care should be taken if patients have hemoglobinopathy or any red cell abnormalities. Iron deficiency anemia gives false lower values of HbA1C.
2-hour postprandial blood sugar, usually known as 2hr PP sugar is a relic of the past and has no clinical importance in the present-day management of DM. A random sugar test is preferable instead.
Interpretation of Random blood glucose test.
Normal- Glucose less than 140 mg/dL or HbA1C 4.6% or less.
Prediabetic- Glucose between 140 to 200 mg /dL or HbA1C 4.7 % to 6.4 %
Diabetic – Glucose over 200mg /dL or HbA1C over 6.5 %
After the initial diagnosis of DM is made, further tests can be done on an individual. Some of these tests are - the blood level of insulin, insulin antibodies, abnormal structure of circulating insulin, the status of the beta cells of the pancreas, liver function tests, blood level of glucagon, pituitary growth hormones, steroid hormones, etc. In DM type II family history of DM usually is very strong.
[ The formula for conversion of HbA1C into Glucose in mg/dL.
( 28.7 x HbA1C ) - 46.7 = Glucose in mg/dL.
Formula to covert plasma glucose in mg/dL to mmol/L
Glucose in mg / 18. = mmol/L ]
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