Diabetes Mellitus The name “diabetes mellitus means sweet urine. It stems from ancient times when physicians would taste a patients urine as a part of a diagnosis.

Definition Hyperglycemia due to Absolute or relative deficiency of insulin.

What is Diabetes? A condition in which the body cannot make or cannot use insulin properly

Pancreas The pancreas functions as both an exocrine and an endocrine gland Exocrine function is associated with the digestive system . Endocrine Function: produces two important hormones in Islets of Langerhans, insulin and glucagon α –Glucagon Β-Insulin δ-Somatostatin PP-Pancreatic polypeptide Γ-Gastrin

Dr Padghan Dilip R M.D. Medicine DIABETES Dr Padghan Dilip R M.D. Medicine

Insulin Secretion Fig. 47-1

NORMAL CONDITION DIABETIC CONDITION STOMACH Food consumed NORMAL CONDITION MOUTH DIABETIC CONDITION STOMACH Food gets converted into glucose PANCREAS Pancreas make little or no insulin Pancreas make insulin Fat Accumulation BLOOD STREAM BLOOD STREAM Blockage Body is unable to utilize glucose because of impaired action/lack of insulin & glucose concentration in blood raises. Body is able to convert glucose into energy due to the action of insulin (carrier of glucose)

Classification of Diabetes Demographics 25 50 <15 15-30 30-45 45-55 55-70 >70 Current Age Distribution Classification of Diabetes Type 1 7.6% Type 2 90.6% Others 1.9% Age Groups Current Mean Age 53.4 ± 13.0 (n= 2269) Mean Age at Onset of Diabetes 43.6 ± 12.2 (n= 2251) Mean Diabetes Duration 10.0 ± 6.9 (n= 2251) DiabCare Asia India

Types of Diabetes Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Gestational Diabetes Other types: LADA ( MODY (maturity-onset diabetes of youth) Secondary Diabetes Mellitus

Type 1 diabetes Was previously called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes. Type 1 diabetes develops when the body’s immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. This form of diabetes usually strikes children and young adults, although disease onset can occur at any age. Type 1 diabetes may account for 5% to 10% of all diagnosed cases of diabetes. Risk factors for type 1 diabetes may include autoimmune, genetic, and environmental factors.

Gary Hall Jr. Olympic swimming medalist Type 1 diabetes

Pathophysiology Genetic susceptibility Environmental triggers Association with HLA DR3/4, DQ 2/8 alleles Environmental triggers Viruses: congenital rubella, coxsackievirus, enterovirus, mumps Early exposure to cow’s milk

Pathophysiology Autoimmune destruction of pancreatic -cell Antibodies: Islet cell Insulin Anti-glutamic acid decarboxylase 65 T-cell mediated Lymphocytic infiltration

Pathophysiology Genetic susceptibility Environmental triggers Association with HLA DR3/4, DQ 2/8 alleles Association with HLA DR2 is protective Environmental triggers Viruses: congenital rubella, coxsackievirus, enterovirus, mumps Early exposure to cow’s milk

Associated Autoimmune Disorders Thyroid (Hashimoto’s, Graves’): 5-10% Celiac Disease: 6% Addison’s disease: <1%

Type 2 diabetes Was previously called non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. Type 2 diabetes may account for about 90% to 95% of all diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Native Hawaiians or Other Pacific Islanders are at particularly high risk for type 2 diabetes. Type 2 diabetes is increasingly being diagnosed in children and adolescents.

Gestational diabetes A form of glucose intolerance that is diagnosed in some women during pregnancy. Gestational diabetes occurs more frequently among African Americans, Hispanic/Latino Americans, and American Indians. It is also more common among obese women and women with a family history of diabetes. During pregnancy, gestational diabetes requires treatment to normalize maternal blood glucose levels to avoid complications in the infant. After pregnancy, 5% to 10% of women with gestational diabetes are found to have type 2 diabetes. Women who have had gestational diabetes have a 20% to 50% chance of developing diabetes in the next 5-10 years.

Other types of DM Other specific types of diabetes result from specific genetic conditions (such as maturity-onset diabetes of youth), surgery, drugs, malnutrition, infections, and other illnesses. Such types of diabetes may account for 1% to 5% of all diagnosed cases of diabetes.

LADA Latent Autoimmune Diabetes in Adults (LADA) is a form of autoimmune (type 1 diabetes) which is diagnosed in individuals who are older than the usual age of onset of type 1 diabetes. Alternate terms that have been used for "LADA" include Late-onset Autoimmune Diabetes of Adulthood, "Slow Onset Type 1" diabetes, and sometimes also "Type 1.5 Often, patients with LADA are mistakenly thought to have type 2 diabetes, based on their age at the time of diagnosis. Autoimmune (type 1 diabetes) type 2 diabetes

MODY MODY – Maturity Onset Diabetes of the Young MODY is a monogenic form of diabetes with an autosomal dominant mode of inheritance Originally, diagnosis of MODY was based on presence of non-ketotic hyperglycemia in adolescents or young adults in conjunction with a family history of diabetes. However, genetic testing has shown that MODY can occur at any age and that a family history of diabetes is not always obvious.

Secondary DM Secondary causes of Diabetes mellitus include: Acromegaly, Cushing syndrome, Thyrotoxicosis, Pheochromocytoma Chronic pancreatitis, Cancer Drug induced hyperglycemia: Atypical Antipsychotics Beta-blockers - Inhibit insulin secretion. Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium release. Corticosteroids - Cause peripheral insulin resistance and gluconeogensis. Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels. Naicin - They cause increased insulin resistance due to increased free fatty acid mobilization. Phenothiazines - Inhibit insulin secretion. Protease Inhibitors - Inhibit the conversion of proinsulin to insulin. Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased insulin resistance due to increased free fatty acid mobilization.

Normal Insulin Metabolism Promotes glucose transport from the bloodstream across the cell membrane to the cytoplasm of the cell Analogous to a “key” that unlocks the cell door to allow glucose in

Normal Insulin Metabolism  Insulin after a meal: Stimulates storage of glucose as glycogen Inhibits gluconeogenesis Enhances fat deposition in adipose tissue Increases protein synthesis

Normal Insulin Metabolism Fasting state Counter-regulatory hormones (especially glucagon) stimulate glycogen  glucose When glucose unavailable during fasting state Lipolysis (fat breakdown) Proteolysis (amino acid breakdown)

What goes wrong in Diabetes ? Multitude of mechanisms Insulin Regulation Secretion Uptake or breakdown Beta cells damage

ALTERED CHO METABOLISM  Insulin   Glucose Utilization +  Glycogenolysis Hyperglycemia Glucosuria (osmotic diuresis) Polyuria* (and electrolyte imbalance) Polydipsia* * Hallmark symptoms of diabetes

ALTERED PROTEIN METABOLISM  Insulin   Protein Catabolism  Gluconeogenesis (amino acids  glucose) Hyperglycemia Weight Loss and Fatigue

ALTERED FAT METABOLISM  Insulin   Lipolysis  Free fatty acids + ketones Acidosis + Weight Loss

Type 1 Diabetes Mellitus Formerly known as “juvenile onset” or “insulin dependent” diabetes Most often occurs in people under 30 years of age, but may occur at any age. Peak onset between ages 11 and 13

Type 1 Diabetes Mellitus Etiology and Pathophysiology Progressive destruction of pancreatic  cells Autoantibodies cause a reduction of 80% to 90% of normal  cell function before manifestations occur

Type 1 Diabetes Mellitus Etiology and Pathophysiology Causes: Genetic predisposition Enviromental

Type 1 Diabetes Mellitus Onset of Disease Weight loss Polydipsia (excessive thirst) Polyuria (frequent urination) Polyphagia (excessive hunger) Weakness and fatigue Ketoacidosis

Classification of Diabetes Type I DM Type II DM Aetiology Autoimmune (- cell destruction) Insulin resistance and -cell dysfunction Peak age 12 years 60 years Prevalence 0.3% 6% (>10% above 60 years) Presentation Osmotic symptoms, weight loss (days to weeks), DKA Patient usually slim Osmotic symptoms, diabetic complications (months to years). Patient usually obese Treatment Diet and insulin Diet, exercise (weight loss), oral hypoglycemics, Insulin later

Criteria for the Diagnosis of Diabetes A1C ≥6.5% OR Fasting plasma glucose (FPG) ≥126 mg/dl Two-hour plasma glucose ≥200 mg/dl during an OGTT A random plasma glucose ≥200 mg/dl Table 2, current diagnostic criteria for the diagnosis of diabetes, is divided into five slides On this slide, all four criteria are included: A1C ≥6.5% Fasting plasma glucose (FPG) ≥126 mg/dl (7.0 mmol/l) Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT A random plasma glucose ≥200 mg/dl (11.1 mmol/l), in patients with classic symptoms of hyperglycemia or hyperglycemic crisis The subsequent slides examine each of the four criteria in greater detail ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 2. Reference American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S13. Table 2.

Prediabetes: IFG, IGT, Increased A1C Categories of increased risk for diabetes (Prediabetes)* FPG 100-125 mg/dl (5.6-6.9 mmol/l): IFG or 2-h plasma glucose in the 75-g OGTT 140-199 mg/dl (7.8-11.0 mmol/l): IGT A1C 5.7-6.4% In 1997 and 203, The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus1,2 recognized an intermediate group of individuals whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered normal This group was defined as having impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) IFG: fasting plasma glucose (FPG) of 100-125 mg/dl (5.6-5.9 mmol/l) IGT: two-hour plasma glucose (2-h PG) on the 75-g oral glucose tolerance test (OGTT) of 140-199 mg/dl (7.8-11.0 mmol/l) It should be noted that the World Health Organization (WHO) and a number of other diabetes organizations define the cutoff for IFG at 110 mg/dl (6.1 mmol) Individuals with IFG and/or IGT have been referred to as having prediabetes, indicating a relatively high risk for future development of diabetes IFG and IGT should not be viewed as clinical entities in their own right but rather risk factors for diabetes as well as cardiovascular disease (CVD) IFG and IGT are associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension Individuals with an A1C of 5.7-6.4% should be informed of their increased risk for diabetes as well as CVD and counseled about effective strategies to lower their risks (see Prevention/Delay of Type 2 Diabetes) *For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range. ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 3. References Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-1197. Genuth S, Alberti KG, Bennett P, et al., for the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26:3160-3167. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S13. Table 3.

Impaired Fasting Glucose Impaired Glucose Tolerance What is pre-diabetes? Impaired Fasting Glucose Impaired Glucose Tolerance

Revised Diagnostic Criteria Standards of Medical Care in Diabetes--2007. Diabetes Care 30:S4-S41, 2007

Is pre-diabetes dangerous? Yes. Around 40-50 % of pre-diabetics eventually progress to develop DM at the end of 5 yrs. Hence it is recommended to act at this stage itself in order to prevent DM. Pre-diabetes may also be associated with ongoing vascular damage and hence increased risk of micro/macro-vascular complications of DM even before the setting in of high blood sugars.

Monitoring of Blood Sugar Check when and how often to monitor - suggested times include Fasting, before lunch and dinner 2 hrs after breakfast, lunch and dinner 3 AM Test more often When not well Suspect hypoglycemia During pregnancy When changing treatment or not in control

Plasma insulin or C-peptide measurement These estimations are not required in routine clinical practice However they are useful in research in clinical situations such as recurrent hypoglycemia and when clinical classification is difficult Can be done only in specialized laboratories

Burden of Diabetes The development of diabetes is projected to reach pandemic proportions over the next10-20 years. International Diabetes Federation (IDF) data indicate that by the year 2025, the number of people affected will reach 333 million –90% of these people will have Type 2 diabetes. In most Western societies, the overall prevalence has reached 4-6%, and is as high as 10-12% among 60-70-year-old people. The annual health costs caused by diabetes and its complications account for around 6-12% of all health-care expenditure.

The Miracle of Insulin Patient J.L., December 15, 1922 February 15, 1923

Management of Diabetes Mellitus

Banting and Best 1923 Nobel Prize for discovery and use of insulin in the treatment of IDDM

The Miracle of Insulin Patient J.L., December 15, 1922 February 15, 1923

Overview of Insulin and Action

Management of DM A B C Diet and Exercise Insulin Therapy The major components of the treatment of diabetes are: Diet and Exercise A Oral hypoglycaemic therapy B Insulin Therapy C