and Diabetes Metabolic Disease
Paul R. Earl
Facultad de Ciencias Biolgicas Universidad Autnoma de Nuevo Len San Nicols, NL 66450, Mexico [e-mail]
Nicolas Paulescu
Discovery
In the middle of the 19th century, evidence from autopsies started to suggest a link between the pancreas and Diabetes Mellitus. Diabetics were sometimes seen to have pancreas damage, and patients with damaged pancreases almost always had diabetes. In 1869 at 22 years, Paul Langerhans (18471888) discovered the existence of two systems of cells in the pancreas: the acinar cells, secreting the pancreatic juice, mostly trypsin, into the digestive system, and isletsthe islets of Langerhans floating among the acini with an unknown function.
In 1889, Oskar Minkowski (18581931) and Josef Von Mering (18491908) depancreatized a dog, causing a state of polyuria indistinguishable from diabetes. This was the first direct evidence of the link between diabetes and the pancreas. They also showed that it was not the absence of the pancreatic juice that caused diabetes by studying the effect of ligating the pancreatic ducts rather than removing the whole pancreas. In most cases this caused minor digestive problems, but never diabetes.
All roads lead to Minkowski & Von Mering, yet various discoveries had been made through the long centuries. William Prout (17851859) associated coma with diabetes. Georg Ludwig Zlzer's (18701949) unsuccessful toxic pancreatic extract tested in Minkowski's clinic in 1908 was abandoned.
Oskar Minkowski
In 1916, Nicolas Paulescu (18691931) succeeded in developing an aqueous pancreatic extract that normalized a diabetic dog. In 1921, he published 4 papers in the Society of Biology in Paris centering on the successful effects of the pancreatic extract in diabetic dogs. Research on the Role of the Pancreas in Food Assimilation by Paulescu was published in August, 1921 in the Archives Internationales de Physiologie, Lige, Belgium.
Eight months after Paulescu's works were published, Sir Frederick Grant Banting (18911941) and biochemist John James Richard Macleod (18761935) of the University of Toronto published their paper on the successful use of a pancreatic extract for normalizing blood sugar (glucose) levels (hyperglycemia) in diabetic dogs. Their 1922 paper confirms Paulescu's article with direct reference. Banting & Best (18991978) also published then.
Fredrick Sanger and his coworkers sequenced bovine insulin in 1955, and he thus won the Nobel prize in 1980. Read The Discovery of Insulin by Michael Bliss in 1982, University of Chicago Press. Other parts of insulin's unfinished story include the hormones leptin and adiponectin. Helpful information sources are the International Diabetes Federation www.idf.org , the Disease Monitoring and Telecommunication, WHO Collaborating Centre at [e-mail] and Diabesity at www.eurodiabesity.org. Diabesity at www.eurodiabesity.org.
Acini and islets of Langerhans
The parenchyma of the exocrine pancreasis composed of darkstaining serous cells arranged in acini. "Dark" refers to H&E which of course is hemotoxylineosin purple and roseorangebasic vs acidic. Interspersed among these many acini is the endocrine component of the pancreas, ovoid groups of islet cells.
Islet of Langerhans Islet with acinar cells
The central feature: Insulin
Insulin mobilizes glucose for storage. When thousands upon thousands of insulin receptors along the linings of the arteries are lost, even when the pancreas pumps out more insulin, diabetes type 2 or metabolic disease may arise to strongly shorten our lives.
Insulin Resistance occurs when the body can't absorb
glucose Abdominal fatin men with over a 102 cm waist (40 inches) and in women with 89 cm or more (35 inches) High blood sugar levelsat least 110 milligrams per deciliter (mg/dL) after fasting as overnight High triglyceridesat least 150 mg/dL in the blood stream Low high density lipidprotein (HDL, the "good" cholesterol)less than 40 mg/dL if male and 50 mg/dL if female. Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood) Blood pressure of 130/85 mmHg or higher
The actions of insulin include: membrane transport of glucose,
amino acids and certain ions; increased storage of glycogen; formation of triglycerides; stimulation of DNA, RNA and protein synthesis.
Three other peptide hormones are produced in the islets of Langerhans in the pancreas:
glucagon, consisting of 29 amino acids somatostatin, a cyclic 14 amino acids pancreatic polypeptide, 36 amino acids with an amide C terminus
Insulin controls glucose homeostasis by stimulating the uptake of glucose into skeletal muscle and, to a lesser extent, into liver and adipose tissue. In muscle and adipocytes, this uptake is mediated by glucose transporter GLUT4. Other processes in the regulation of glucose balance are: alterations in glycogen metabolism in muscle and liver, and decreased gluconeogenesis in the liver. Perhaps, YOU can improve this understanding. What is glucokinin? What are cytokinins? TOO MUCH INSULIN can cause hypoglycemic shock.
Leptin
Leptin is a 16 kiloDalton protein hormone regulating energy input and utilization. It decreases appetite and increases metabolism. In 1994, leptin discovered was in mice by Jeffrey M Friedman and coworkers at Rockefeller University, NYC. The obesity Ob gene in mice is called the Lep gene in humans. Leptin is produced by adipose tissue, having 6 different types of receptos.
Adiponectin
Adiponectin is a protein hormone that regulates glucose and fatty acid catabolism. Produced by adipocytes, it can be involed in vascular deteriorization. It was discovered in 1997 by Yuji M Matsuzawa and his coworkers. Its APM1 gene maps to chromosome 3q27. Among other actions, adiponectin inhibits the myelomonocytic lineage cells. Itis a negative regulaton in the hemotopoiesis and immune system, thus antiinflamatory.
Metabolic disease
In his book Syndrome X: Overcoming the Silent Killer That Can Give you a Heart Attack (2000, Simon & Schuster, New York), Gerald Reaven gives the history of his discovery of Metabolic Syndrome. "This deadly heart ailment begins in the bloodstream, shortly after we eat. We know that eating fatty or cholesterol-laden foods can be bad for our hearts. However, the Metabolic Syndrome culprit is carbohydrates. Yet these are reluctant, inadvertent offenders.
Environmental Genetic
The Metabolic Syndrome
Obesity
Overeating and then overweight often lead to diabetes. Note that regular exercise maintains and improves health. This worldwide social problem began by the 1980s via sedentary life, fast foods and other changes in life style. Obese persons are more likely to suffer from one or more of several disorders. These include:
diabetes mellitus, type 2 high blood pressure high levels of cholesterol and triglycerides gout gall bladder and urinary calculus osteoarthritis in the back, knees and feet coronary heart disease stroke cancer of the colon and prostate in men, and of the breasts, uterus and polycystic ovaries in women
Averages using adult Mexicans of the north (N) and the south (S) as anthropometric examples are: Height Weight Waist m kg cm N Men 1.69 77.2 95.8 N Women 1.56 69.2 94.7 S Men 1.62 69.5 91.6 S Women 1.50 62.0 92.3
Diabetes Type 1
Type I diabetes mellitus is insulindependent, autoimmune disease. The disease is organspecific resulting in pancreatic islet cell destruction. Evidence of cellular destruction includes autoantibodies to 1) islet cells (ICA), 2) antibodies to insulin (IAA) and 3) glutamic acid decarboxylase autoantibodies (GAD Ab). ICA (as detected on thin frozen sections of human pancreas by indirect immunofluorescence) are present in about 80 % of newly diagnosed patients. ICA, GAD Ab and IAA are each helpful in screening firstdegree relatives of patients with IDDM.
Diabetes Type 2
Type 2 is also caused by insulin deficiency, even though the pancreas is producting it. The cause of morbidity is insulin resistance with consequent hyperglycemia. While diabetes cannot be cured, it can be controlled by insulin, diet, weight control and physical fitness by running, walking and sports. Overeating can sometimes result in diabetes.
Glucose tolerance test
After an overnight fast, a sample of blood is drawn. Then 75 g of glucose dissolved in about 200300 ml of water is drunk. Two hours later another blood sample is taken. Account is taken of the fact that the concentration of glucose measured in plasma is 10 % higher than in whole blood. Diabetes is present when the fasting blood sample is over 6.7 mmol/L or the level in plasma is over 7.8 mmol/L, or the second sample has 10 mmol/L of blood. In healthy persons, the glucose concentration rises to about twice the normal level within the first hour and returns to normal within 2 hours.
Cholesterol test
Cholesterols and triglycerols are types of fats called lipids. Too much fat increases your risk of a heart attack or vascular diseases. Heart disease is the # 1 killer of both men and women. Low density lipoprotein (LDL) cholesterol at abnormally high levels can cause fatty deposits in the arteries which is defined as atheroscelosis, High density lipoprotein (HDL) cholesterol can help carry away LDLs, keeping arteries open. Some triglycerides may result from extra calories.
The cholesterol test depends on fasting for 712 hours. Normal total cholesterol is < 200 mg/dL/. Borderline cases have 200239, and abnormal cases have > 240 mg/dL. Levels of LDL are < 129, 130149 and > 150 mg/dL. Levels of HDL (the "good" cholesterol) are < 149, 150 199 and > 200 mg/dL. Trigylcerides have < 149, 150199 and > 200 mg/dL. New tests based on nuclear resonance are coming along.
Closing remarks
The definitions and additional information supplied in this lecture give you the necessary basic "Introduction to Diabetes." Your task now can be to amplify this information and to follow the lightning pace of diabetes research. A major yet recent trend in life style in the direction of fast highenergy foods can lead to obesity and also diabetes, while chronic malnutrition with stunting continues in very many worldwide rural populations. Ecology including the global warming trend has not been even touched upon here. Of course, such topics deserve their place in the diabetes curriculum.