DIABETES MELLITUS

Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia

History
Diabetes siphon - liquefaction of the flesh and bones into urine coined by Arateus AD 150 1st description 3000 BC polyuria by Imphotep Susruta 400BC- honeyed urine 1776 Matthew dobson- sugar in urine Rollo diet rich in protein and low in carbohydrate as treatment

 1889 -Von Mering and Oscar Minkowski Pancreas as cause diabte maigre (diabetes of the thin) and diabte gras (diabetes of the fat) 1893 Langerhan - Islets 1910 -Jean de Meyer -coined Insulin - from the insulae of Langerhans Banting and Best, Mcleod, Collip 1921 extracted insulin

1st patient to receive Leonard Thompson Sanger insulin structure 1982 Human insulin Lilly Co 1st islet transplant 1989 Lacy and co

CLASSIFICATION
Type 1 diabetes Type 2 diabetes Other specific types of diabetes e.g., genetic defects in cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug-or chemical-induced (such as in the treatment of HIV/AIDS or after organ transplantation) Gestational diabetes mellitus

TYPE -1
Low or absent endogenous insulin Dependent on exogenous insulin for life Onset generally < 30 years 5-10% of cases of diabetes

TYPE 2
Insulin levels may be normal, elevated or depressed
Characterized by insulin resistance, diminished tissue sensitivity to insulin, and impaired beta cell function (delayed or inadequate insulin release)

Often occurs >40 years

RISK FACTORS
Family history of diabetes (i.e., parent or sibling with type 2 diabetes) Obesity (BMI 25 kg/m2) Physical inactivity Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Previously identified with IFG, IGT, or an A1C of 5.76.4% History of GDM or delivery of baby >4 kg (9 lb) Hypertension (blood pressure 140/90 mmHg) HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L) Polycystic ovary syndrome or acanthosis nigricans History of cardiovascular disease

INSULIN
Carbohydrate
Facilitates the transport of glucose into muscle and adipose cells Facilitates the conversion of glucose to glycogen for storage in the liver and muscle. Decreases the breakdown and release of glucose from glycogen by the liver

 Protein
Stimulates protein synthesis Inhibits protein breakdown; diminishes gluconeogenesis

 Fat
Stimulates lipogenesis- the transport of triglycerides to adipose tissue Inhibits lipolysis prevents excessive production of ketones or ketoacidosis

Pathophysiology
HLA DR3 and/or DR4

 3-4% chance if one parent with Type1 5-15% chance if one sibling Type 1 :
Insulitis Auto antibodies- Islet cell antibody anti GAD all beta cells are destroyed Environmental triggers - viruses (coxsackie, rubella, enteroviruses), bovine milk proteins, and nitrosourea compounds.

 Impaired insulin secretion glucotoxicity, lipotoxicity - cell destruction gluconeogenesis, glycogen storage, lipolysis and free fatty acid flux - TG,LDL, HDL Metabolic syndrome visceral obesity

COMPLICATIONS
ACUTE :
DKA

Diabetic ketoacidosis:
Usually with type 1 , also in type 2 during stress

Inadequate insulin treatment or noncompliance New onset diabetes (20-25 percent) Infection (30-40 percent) Myocardial infarction Acute pancreatitis Drugs Clozapine or olanzapine Cocaine Lithium Terbutaline

Insulin deficiency/resistance Acute illness Glucagon excess

Ppt factors Cerebralvascular accident

Features
Hyperglycemia :
Impaired glucose utilization in peripheral tissues Increased gluconeogenesis (both hepatic and renal) Increased glycogenolysis

Dehydration- osmotic diuresis Ketosis :

Enhanced lipolysis in insulin deficiency Free fatty acyl coA beta oxidation to Acetone

 Due to glucagon excess

FFA enters mitochondria with help of CPT1( whose activity 1/ to malonyl coA) Glucagon malonyl coA.

plasma osmolarity cellular dehydation High anion gap acidosis

HONK: Plasma glucose >600mg/dl, no ketosis, plsma osmolality >380mosm

Hypoglycemia

Chronic complications

 Depends on duration and degree of hyperglycemia

increased intracellular glucose leads to the formation of advanced glycosylation end products hyperglycemia increases glucose metabolism via the sorbitol pathway formation of diacylglycerol leading to activation of protein kinase C -the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins

Ophthalmologic

Pathophysiology

loss of retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which lead to retinal ischemia. neovascularization in response to retinal hypoxemia

Nephropathy

Neuropathy
Distal symmetric polyneuropathy Cranial and peripheral nerve involvement causing focal mononeuropathies - oculomotor nerve (cranial nerve III) and the median nerve Autonomic neuropathy Thoracic and lumbar nerve root disease, causing polyradiculopathies Asymmetric involvement of multiple peripheral nerves, resulting in a mononeuropathy multiplex

Autonomic neuropathy

Abnormal pupillary function Sudomotor dysfunction Genitourinary autonomic neuropathy Bladder dysfunction Sexual dysfunction Gastrointestinal autonomic neuropathy Gastric atony Gall bladder atony Diabetic diarrhea Hypoglycemic unawareness (adrenal medullary neuropathy) Cardiovascular autonomic neuropathy Hypoglycemic unawareness

Macrovascular
CAD :
dyslipidemia, hypertension, obesity, reduced physical activity microalbuminuria, macroalbuminuria, an elevation of serum creatinine, and abnormal platelet function endothelial, vascular smooth-muscle, and platelet dysfunction

 Lower extremity complications:

neuropathy, abnormal foot biomechanics, PAD, and poor wound healing Motor and sensory neuropathy lead to abnormal foot muscle mechanics and to structural changes in the foot (hammer toe, claw, toe deformity, prominent metatarsal heads, Charcot joint) Autonomic neuropathy results in anhidrosis and altered superficial blood flow in the foot, which promote drying of the skin and fissure formation

INFECTIONS
Abnormalities in cell-mediated immunity and phagocyte function associated with hyperglycemia, as well as diminished vascularization. Hyperglycemia aids the colonization and growth

 Infections exclusive to diabetics

Malignant otitis externa Rhino-cerebral mucor-mycosis Emphysematous pyelonephritis Emphysematous cholecystitis

Others:
UTI E.coli, candida Carbuncle , furunculosis Pneumonia usual org

Dermatologic
Delayed wound healing Diabetic dermopathy pretibial pigmented spots Diabeticorum bullosum Necrobiosis lipoidica diabeticorum Acanthosis nigricans Granuloma annulare Lipoatrophy ,lipo hypertrophy Scleredema

Clinical features
Osmotic symptoms polyuria, polydypsia
Polyphagia , weight loss

Delayed wound healing Unusual infections or reccurent infections

DKA
Symptoms Nausea/vomiting Thirst/polyuria Abdominal pain Shortness of breath
Physical Findings Tachycardia Dehydration/hypotension Tachypnea/Kussmaul respirations/respiratory distress Abdominal tenderness (may resemble acute pancreatitis or surgical abdomen) Lethargy/obtundation/cerebral edema/possibly coma

 Symptoms of chronic complications

Neuropathy peripheral n ,autonomic Nephropathy Retinopathy

Investigations
Plasma glucose
FPG 70 100 mg/dl (whole blood 65-95mg/dl)
IGT 100 125mg/dl Diabetes - 126mg/dl

2h post prandial 70 -139mg/dl

IGT 140 199mg/dl Diabetes - 200mg/dl

HbA1c glycated hemoglobin - remains same for life of RBC- 120 days
Average glucose = 28.7 A1C 46.7

HbA1c (%) 5 6

eAG (estimated average glucose) (mg/dL) 97 (76120) 126 (100152)

7
8 9 10 11 12

154 (123185)
183 (147217) 212 (170249) 240 (193282) 269 (217314) 298 (240347)

 C-peptide
0.51-2.72 ng/ml

Plasma glucose and blood glucose

Glucose is dissolved in water. The plasma phase of blood has a higher concentration of water (~93%) compared to that of red blood cells (~71%). Therefore plasma has a higher glucose concentration than that of whole blood Plasma glucose = blood glucose 1.11 at normal PCV

Criteria for the Diagnosis of Diabetes Mellitus

Symptoms of diabetes plus random blood glucose concentration 11.1 mmol/L (200 mg/dL)aor Fasting plasma glucose 7.0 mmol/L (126 mg/dL)bor A1C > 6.5%cor Two-hour plasma glucose 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testd

Detection of complications
DKA :
Urine ketones
Urine value 0 1+ 2+ 3+ 4+ Severe ketonuria Ketonuria Designation Approximate serum concentration mg/dL Negative Reference range: 0.5-3.0 5 (IQR): 1-9) 7 (IQR: 2-19) 30 (IQR: 14-54) -

 Blood ketone - Negative: < 1 mg/dL ABG pH , HCO3

Anion gap 7-16mmol/L

Electrolytes esp K+ , Na Renal function For ppt factor cultures, total count, CXR, ECG

Chronic complications:
Nephropathy microalbuminuria 30 -300mg/d
>300mg/d- macroalbuminuria Creatinine /BUN

 Neuropathy:
VPT NCV Urodynamic study Gastric transit

Retinopathy
Fundoscopy Fluorescin angiography

Ecg ,TMT, Ankle Brachial Index

TREATMENT

Nutritional Recommendations for Adults with Diabetes

Weight loss diet (in prediabetes and type 2 DM) Hypocaloric diet that is low-fat or low-carbohydrate Fat in diet Minimal trans fat consumption Carbohydrate in diet Monitor carbohydrate intake in regards to calories Sucrose-containing foods may be consumed with adjustments in insulin dose Amount of carbohydrate determined by estimating grams of carbohydrate in diet for (type 1 DM) Glycemic index reflects how consumption of a particular food affects the blood glucose Protein in diet: as part of an optimal diet Other components Nonnutrient sweeteners Routine supplements of vitamins, antioxidants, or trace elements not advised

 Physical exercise:
perform at least 150 min/week of moderateintensity aerobic physical activity (50 70% of maximum heart rate) resistance training three times per week if no C/I

Insulins

 Subcutaneous/ IM/IV Insulin pumps Buccal sprays

Oral hypoglycemic agents

Biguanides: Metformin
hepatic glucose output, peripheral utilisation Adr vomiting, lactic acidosis C/I- in renal failure, CHF, Sepsis

-glucosidase inh: Acarbose, Miglitol, Voglibose

GI glucose absorption - postprandial glycemia Adr bloating C/I renal/hepatic failure

 Dipeptidyl peptidase IV inhibitors: prolong GLP1 action Sitagliptin, vildagliptin Insulin secretagogues:
Sulfonyl-ureas:
Glimepiride Glipizide Glyburide

Non sulfonyl-urea
Repaglinide Nateglinide

 Thiazolidinediones: Pioglitazone,Rosiglitazone
insulin resistance, peripheral utilisation Adr- edema, CHF, weight gain

Other parenteral
GLP1 receptor agonist: Exenatide , Liraglutide
insulin , glucagon, slow gastric emptying weight loss Adr nausea

Amylin agonist Pramlintide

Slow gastric emptying , glucagon

Guidelines for Ongoing Medical Care for Patients with Diabetes

Self-monitoring of blood glucose (individualized frequency) A1C testing (24 times/year) Patient education in diabetes management (annual) Medical nutrition therapy and education (annual) Eye examination (annual) Foot examination (12 times/year by physician; daily by patient) Screening for diabetic nephropathy (annual; see Fig. 344-11) Blood pressure measurement (quarterly) Lipid profile and serum creatinine (estimate GFR) (annual) Influenza/pneumococcal immunizations Consider antiplatelet therapy (see text)

DKA
Maintain ABC Replace fluids nearly 6 litres deficit Insulin infusion 0.1 units/kg per hour titrate to blood glucose Correct dyselectrolemia K+ Sodabicarb? Correct ppt factor antibiotic Monitor BG hourly, electrolytes 4 hourly

 Nephropathy
ACE inhibitors BP control Glycemic control

Retinopathy Laser photocoagulation

Neuropathy
B12, folate, pyridoxine Glycemic control Amitryptiline , pregabalin ,gabapentin

 Foot care
Treat infections Daily inspection for injuries Special footwares

Newer therapies
Islet cell transplant Pancreatic transplant Stem cell therapy