Nicolas PaulescuNicolas Paulescu

Diabetes and Metabolic Diabetes and Metabolic DiseaseDisease

Paul R. EarlPaul R. EarlFacultad de Ciencias BiológicasFacultad de Ciencias Biológicas

Universidad AutónomaUniversidad Autónoma de Nuevo León de Nuevo León

San Nicolás, San Nicolás, NL 66450, MexicoNL 66450, Mexico pearl@dsi.uanl.mx

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 (1847-1888) 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 islets--the islets of Langerhans--floating among the acini with an unknown function.

Discovery

In 1889, Oskar Minkowski (1858-1931) and Josef Von Mering (1849-1908) 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 (1785-1859) associated coma with diabetes. Georg Ludwig Zülzer's (1870-1949) unsuccessful toxic pancreatic extract tested in Minkowski's clinic in 1908 was abandoned.

Oskar Minkowski

In 1916, Nicolas Paulescu (1869-1931) 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 Assimil-ation by Paulescu was published in August, 1921 in the Archives Internationales de Physiologie, Liège, Belgium.

Eight months after Paulescu's works were published, Sir Frederick Grant Banting (1891-1941) and biochemist John James Richard Macleod (1876-1935) 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 (1899-1978) also published then.

Fredrick Sanger and his coworkers Fredrick Sanger and his coworkers sequenced bovine insulin in 1955, and he sequenced bovine insulin in 1955, and he thus won the Nobel prize in 1980. Read thus won the Nobel prize in 1980. Read The Discovery of Insulin The Discovery of Insulin by Michael Bliss by Michael Bliss in 1982, University of Chicago Press.in 1982, University of Chicago Press.Other parts of insulin's unfinished story Other parts of insulin's unfinished story include the hormones leptin and include the hormones leptin and adiponectin. adiponectin. Helpful information sources Helpful information sources are the International Diabetes Federation are the International Diabetes Federation www.idf.org , the Disease Monitoring and , the Disease Monitoring and Telecommunication, WHO Collaborating Telecommunication, WHO Collaborating Centre at Centre at super1@pitt.edu and Diabesity at and Diabesity at www.eurodiabesity.org.www.eurodiabesity.org.

The parenchyma of the exocrine pancreasis composed of dark-staining serous cells arranged in acini. "Dark" refers to H&E which of course is hemotoxylin-eosin--purple and rose-orange--basic vs acidic. Interspersed among these many acini is the endocrine component of the pancreas, ovoid groups of islet cells.

Acini and islets of Langerhans

Islet of Langerhans

Islet with acinar cells

Insulin mobilizes glucose for Insulin mobilizes glucose for storage. When thousands upon storage. When thousands upon thousands of insulin receptors thousands of insulin receptors along the linings of the arteries along the linings of the arteries are lost, even when the are lost, even when the pancreas pumps out more pancreas pumps out more insulin, diabetes type 2 or insulin, diabetes type 2 or metabolic disease may arise to metabolic disease may arise to strongly shorten our lives.strongly shorten our lives.

The central feature: InsulinThe central feature: Insulin

Insulin ResistanceInsulin Resistance occurs when the body can’t occurs when the body can’t absorb glucose absorb glucose Abdominal fat–in men with over a 102 cm Abdominal fat–in men with over a 102 cm waist (40 inches) and in women with 89 cm or waist (40 inches) and in women with 89 cm or more (35 inches)more (35 inches)High blood sugar levels–at least 110 High blood sugar levels–at least 110 milligrams per deciliter (mg/dL) after fasting as milligrams per deciliter (mg/dL) after fasting as overnight overnight High triglycerides–at least 150 mg/dL in the High triglycerides–at least 150 mg/dL in the blood stream blood stream Low high density lipidprotein (HDL, the “good” Low high density lipidprotein (HDL, the “good” cholesterol)–less than 40 mg/dL if male and 50 cholesterol)–less than 40 mg/dL if male and 50 mg/dL if female. mg/dL if female. Prothrombotic state (e.g., high fibrinogen or Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood) plasminogen activator inhibitor in the blood)

Blood pressure of 130/85 mmHg or higherBlood pressure of 130/85 mmHg or higher

The actions of insulin include:The actions of insulin include:

membrane transport of membrane transport of glucose, glucose, amino acids and certain ions; amino acids and certain ions; increased storage of glycogen; increased storage of glycogen; formation of triglycerides; formation of triglycerides; stimulation of DNA, RNA and stimulation of DNA, RNA and protein synthesis. protein synthesis.

Three other peptide Three other peptide hormones are produced in hormones are produced in the islets of Langerhans in the islets of Langerhans in the pancreas: the pancreas:

--glucagon, consisting of 29 glucagon, consisting of 29 amino acids amino acids -somatostatin, a cyclic 14 amino -somatostatin, a cyclic 14 amino acids acids --pancreatic polypeptide, 36 pancreatic polypeptide, 36 amino acids with an amide C amino acids with an amide C terminus terminus

Insulin controls glucose homeostasis by Insulin controls glucose homeostasis by stimulating the uptake of glucose into stimulating the uptake of glucose into skeletal muscle and, to a lesser extent, into skeletal muscle and, to a lesser extent, into liver and adipose tissue. In muscle and liver and adipose tissue. In muscle and adipocytes, this uptake is mediated by adipocytes, this uptake is mediated by glucose transporter GLUT-4. Other processes glucose transporter GLUT-4. Other processes in the regulation of glucose balance are: in the regulation of glucose balance are: alterations in glycogen metabolism in alterations in glycogen metabolism in muscle and liver, and decreased muscle and liver, and decreased gluconeogenesis in the liver. Perhaps, gluconeogenesis in the liver. Perhaps, YOU YOU can improve this understanding. What is can improve this understanding. What is glucokinin? What are cytokinins? glucokinin? What are cytokinins?

TOO MUCH INSULIN can cause hypoglycemic TOO MUCH INSULIN can cause hypoglycemic shock.shock.

LeptinLeptin

Leptin is a 16 kiloDalton protein Leptin is a 16 kiloDalton protein hormone regulating energy input and hormone regulating energy input and utilization. It decreases appetite and utilization. It decreases appetite and increases metabolism. In 1994, leptin increases metabolism. In 1994, leptin was discovered in mice by Jeffrey M was discovered in mice by Jeffrey M Friedman and coworkers at Friedman and coworkers at Rockefeller University, NYC. Rockefeller University, NYC.

The obesity The obesity ObOb gene in mice is called gene in mice is called the the LepLep gene in humans. Leptin is gene in humans. Leptin is produced by adipose tissue, having 6 produced by adipose tissue, having 6

different types of receptos.different types of receptos.

AdiponectinAdiponectin

Adiponectin is a protein hormone that Adiponectin is a protein hormone that regulates glucose and fatty acid regulates glucose and fatty acid catabolism. Produced by adipocytes, it catabolism. Produced by adipocytes, it can be involed in vascular deteriorization. can be involed in vascular deteriorization.

It was discovered in 1997 by Yuji M It was discovered in 1997 by Yuji M Matsuzawa and his coworkers. Its APM1 Matsuzawa and his coworkers. Its APM1 gene maps to chromosome 3q27. Among gene maps to chromosome 3q27. Among other actions, adiponectin inhibits the other actions, adiponectin inhibits the myelomonocytic lineage cells. Itis a myelomonocytic lineage cells. Itis a negative regulaton in the hemotopoiesis negative regulaton in the hemotopoiesis and immune system, thus antiinflamatory. and immune system, thus antiinflamatory.

In his book In his book Syndrome X: Overcoming Syndrome X: Overcoming the Silent Killer That Can Give you a the Silent Killer That Can Give you a Heart AttackHeart Attack (2000, Simon & Schuster, (2000, Simon & Schuster, New York), Gerald Reaven gives the New York), Gerald Reaven gives the history of his discovery of Metabolichistory of his discovery of MetabolicSyndrome.Syndrome."This deadly heart ailment begins in the "This deadly heart ailment begins in the bloodstream, shortly after we eat. We know that bloodstream, shortly after we eat. We know that eating fatty or cholesterol-laden foods can be eating fatty or cholesterol-laden foods can be bad for our hearts. However, the Metabolic bad for our hearts. However, the Metabolic Syndrome culprit is carbohydrates. Yet these Syndrome culprit is carbohydrates. Yet these are reluctant, inadvertent offenders.are reluctant, inadvertent offenders.

Metabolic diseaseMetabolic disease

The Metabolic SyndromeThe Metabolic SyndromeEnvironmental GeneticEnvironmental Genetic

ObesityObesityOvereating and then overweight often lead to Overeating and then overweight often lead to diabetes. Note that regular exercise maintains and diabetes. Note that regular exercise maintains and improves health. This worldwide social problem improves health. This worldwide social problem began by the 1980s via sedentary life, fast foods began by the 1980s via sedentary life, fast foods and other changes in and other changes in life stylelife style. . Obese persons are more likely to suffer from one Obese persons are more likely to suffer from one or more of several disorders. or more of several disorders. These include:These include:-diabetes mellitus, type 2-diabetes mellitus, type 2-high blood pressure-high blood pressure--high levels of cholesterol and triglycerides high levels of cholesterol and triglycerides --goutgout-gall bladder and urinary calculus-gall bladder and urinary calculus--osteoarthritis in the back, knees and feetosteoarthritis in the back, knees and feet--coronary heart diseasecoronary heart disease-stroke-stroke--cancer of the colon and prostate in men, and of the cancer of the colon and prostate in men, and of the breasts, uterus and polycystic ovaries in womenbreasts, uterus and polycystic ovaries in women

Averages using adult Mexicans of the Averages using adult Mexicans of the north (N) and the south (S) as north (N) and the south (S) as anthropometric examples are: anthropometric examples are:

Height Weight WaistHeight Weight Waist m kg cm m kg cm

N Men 1.69 77.2 95.8 N Men 1.69 77.2 95.8 N Women 1.56 69.2 94.7 N Women 1.56 69.2 94.7 S Men 1.62 69.5 91.6 S Men 1.62 69.5 91.6 S Women 1.50 62.0 92.3 S Women 1.50 62.0 92.3

Diabetes Type 1Diabetes Type 1

Type I diabetes mellitus is insulin-dependent, Type I diabetes mellitus is insulin-dependent, autoimmune disease. The disease is organ-autoimmune disease. The disease is organ-specific resulting in pancreatic islet cell specific resulting in pancreatic islet cell destruction. Evidence of cellular destruction destruction. Evidence of cellular destruction includes autoantibodies to 1) islet cells (ICA), includes autoantibodies to 1) islet cells (ICA), 2) antibodies to insulin (IAA) and 3) glutamic 2) antibodies to insulin (IAA) and 3) glutamic acid decarboxylase autoantibodies (GAD Ab).acid decarboxylase autoantibodies (GAD Ab).

ICA (as detected on thin frozen sections of ICA (as detected on thin frozen sections of human pancreas by indirect human pancreas by indirect immunofluorescence) are present in about 80 immunofluorescence) are present in about 80 % of newly diagnosed patients. ICA, GAD Ab % of newly diagnosed patients. ICA, GAD Ab and IAA are each helpful in screening first-and IAA are each helpful in screening first-degree relatives of patients with IDDM. degree relatives of patients with IDDM.

Diabetes Type 2Diabetes Type 2

Type 2 is also caused by insulin Type 2 is also caused by insulin deficiency, even though the pancreas deficiency, even though the pancreas is producting it. The cause of is producting it. The cause of morbidity is morbidity is insulin resistance insulin resistance with with consequent hyperglycemia. While consequent hyperglycemia. While diabetes cannot be cured, it can be diabetes cannot be cured, it can be controlled by insulin, diet, weight controlled by insulin, diet, weight control and physical fitness by control and physical fitness by running, walking and sports. running, walking and sports. Overeating can sometimes result in Overeating can sometimes result in diabetes. diabetes.

Glucose tolerance testGlucose tolerance test

After an overnight fast, a sample of blood is After an overnight fast, a sample of blood is drawn. Then 75 g of glucose dissolved in about drawn. Then 75 g of glucose dissolved in about 200-300 ml of water is drunk. Two hours later 200-300 ml of water is drunk. Two hours later another blood sample is taken. Account is another blood sample is taken. Account is taken of the fact that the concentration of taken of the fact that the concentration of glucose measured in plasma is 10 % higher glucose measured in plasma is 10 % higher than in whole blood.than in whole blood.Diabetes is present when the fasting blood Diabetes is present when the fasting blood sample is over 6.7 mmol/L or the level in sample is over 6.7 mmol/L or the level in plasma is over 7.8 mmol/L, or the second plasma is over 7.8 mmol/L, or the second sample has 10 mmol/L of blood.sample has 10 mmol/L of blood.In healthy persons, the glucose concentration In healthy persons, the glucose concentration rises to about twice the normal level within the rises to about twice the normal level within the first hour and returns to normal within 2 hours. first hour and returns to normal within 2 hours.

Cholesterols and triglycerols are types of Cholesterols and triglycerols are types of fats called fats called lipids. lipids. Too much fat increases Too much fat increases your risk of a heart attack or vascular your risk of a heart attack or vascular diseases. Heart disease is the # 1 killer of diseases. Heart disease is the # 1 killer of both men and women.both men and women.

Low density lipoprotein (LDL) cholesterol at Low density lipoprotein (LDL) cholesterol at abnormally high levels can cause fatty abnormally high levels can cause fatty deposits in the arteries which is defined as deposits in the arteries which is defined as atheroscelosis,atheroscelosis,

High density lipoprotein (HDL) cholesterol High density lipoprotein (HDL) cholesterol can help carry away LDLs, keeping arteries can help carry away LDLs, keeping arteries open. Some triglycerides may result from open. Some triglycerides may result from extra calories.extra calories.

Cholesterol testCholesterol test

The cholesterol test depends on fasting for 7-The cholesterol test depends on fasting for 7-12 hours. Normal total cholesterol is < 200 12 hours. Normal total cholesterol is < 200 mg/dL/. Borderline cases have 200-239, and mg/dL/. Borderline cases have 200-239, and abnormal cases have > 240 mg/dL.abnormal cases have > 240 mg/dL.

Levels of LDL are < 129, 130-149 and > 150 Levels of LDL are < 129, 130-149 and > 150 mg/dL.mg/dL.

Levels of HDL (the "good" cholesterol) are < Levels of HDL (the "good" cholesterol) are < 149, 150-199 and > 200 mg/dL.149, 150-199 and > 200 mg/dL.

Trigylcerides have < 149, 150-199 and > 200 Trigylcerides have < 149, 150-199 and > 200 mg/dL.mg/dL.

New tests based on nuclear resonance are New tests based on nuclear resonance are coming along.coming along.

The definitions and additional information The definitions and additional information supplied in this lecture give you the necessary supplied in this lecture give you the necessary basic "Introduction to Diabetes." Your task now basic "Introduction to Diabetes." Your task now can be to amplify this information and to follow can be to amplify this information and to follow the lightning pace of diabetes research.the lightning pace of diabetes research.

A major yet recent trend in life style in the A major yet recent trend in life style in the direction of fast high-energy foods can lead to direction of fast high-energy foods can lead to obesity and also diabetes, while chronic obesity and also diabetes, while chronic malnutrition with stunting continues in very malnutrition with stunting continues in very many worldwide rural populations. Ecology many worldwide rural populations. Ecology including the global warming trend has not including the global warming trend has not been even touched upon here. Of course, such been even touched upon here. Of course, such topics deserve their place in the diabetes topics deserve their place in the diabetes curriculum. curriculum.

Closing remarksClosing remarks