DIABETES DIABETES MELLITUSMELLITUS

DR AFTAB AHMED RAJPUT DR AFTAB AHMED RAJPUT FCPS PART 2 TRAINEE FCPS PART 2 TRAINEE

MEDICAL UNIT 2MEDICAL UNIT 2PMCH,NAWAB SHAHPMCH,NAWAB SHAH

PRESENTATION OUTLINES

DM AND ITS CLASSIFICATIONPATHOPHYSIOLOGY OF DMCLINICAL FEATURES OF DMINVESTIGATIONSDIAGNOSTIC CRITERIA FOR DM MANAGEMENT OF DM

DIABETES MELITUS…a metabolic disorder of multiple aetiology

characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both

CURRENT IMPACT OF DM 66thth leading cause of death by disease leading cause of death by disease Decreases life expectancy of middle-aged people by Decreases life expectancy of middle-aged people by

5-10 years5-10 years• 2-4 x greater risk of death d/t heart disease2-4 x greater risk of death d/t heart disease

Compounding factors include: duration of disease, Compounding factors include: duration of disease, glycemic control, HTN, smoking, dyslipidemia, decreased glycemic control, HTN, smoking, dyslipidemia, decreased activity, and obesityactivity, and obesity

Leading cause of blindness in 25-74 year oldsLeading cause of blindness in 25-74 year olds Leading cause of non-traumatic amputationsLeading cause of non-traumatic amputations Responsible for 25-30% of all new dialysis patientsResponsible for 25-30% of all new dialysis patients

CLASSIFICATION OF DM

TRADITIONALY DM HAS BEEN DIVIDED INTO PRIMARY DM IN WHICH THERE IS DEFECT IN INSULIN PRODUCTION

AND/OR ITS ACTION 2NDRY IN WHICH ANY DISEASE CAUSES EXTENSIVE

DEMAGE OF PANCREATIC ISLET e.g,pancratitis,tumors,drugs,iron overload ,surgical removal of pancreatic substance and certain endocrinopathies that antagonize the action of insulin.

CLASSIFICATIONIn 1997 AMERICAN DIABETES ASSOCIATION

RECOMMENDED A NEW CLASSIFICATION BASED ON ETIOLOGY.

THERE IS NO DISTINCTION BETWEEN PRIMARY AND 2NDRY DM AND DESCRIPTION BASED ON AGE OF ONSET OR TYPE OF TREATMENT HAVE BEEN ELIMINATED.

CONTI……..1. Type 1 diabetes (b-cell destruction, leads to absolute insulin deficiency)

•Immune-mediated (TYPE 1A) •Idiopathic (TYPE 1B)2. Type 2 diabetes (insulin resistance with relative insulin deficiency)3. Genetic defects of b-cell function •Maturity-onset diabetes of the young (MODY), caused by mutations in:

•Hepatocyte nuclear factor 4a [HNF-4a] (MODY1)\•Glucokinase (MODY2)•Hepatocyte nuclear factor 1a [HNF-1a] (MODY3)•Insulin promoter factor [IPF-1] (MODY4)•Hepatocyte nuclear factor 1b [HNF-1b] (MODY5)•Neurogenic differentiation factor 1 [Neuro D1] (MODY6)•Mitochondrial DNA mutations

CONTI……4. Genetic defects in insulin processing or insulin action•Defects in proinsulin conversion•Insulin gene mutations•Insulin receptor mutations5. Exocrine pancreatic defects•Chronic pancreatitis•Pancreatectomy•Neoplasia•Cystic fibrosis•Hemachromatosis•Fibrocalculous pancreatopathy6. Endocrinopathies• Cushing syndrome• Hyperthyroidism• Pheochromocytoma• Glucagonoma• Acromegaly

CONTI……• 7. Infections• Rubella• Cytomegalovirus• Coxsackie virus B• Epstein barr virus• 8. Drugs Glucocorticoids interferon Protease inhibitors b-adrenergic agonists Thiazides Nicotinic acid9. Genetic syndromes associated with diabetes• Down syndrome• Kleinfelter syndrome• Turner syndrome• 10. Gestational diabetes mellitus

PATHOPHYSIOLOGGY OF DM• The pancreas functions as both an exocrine and an

endocrine gland• Exocrine function is associated with the digestive

system because it produces and secretes digestive enzymes

• Endocrine Function: produces two important hormones in Islets of Langerhans, insulin and glucagon– They work together to maintain a steady level of glucose, or sugar, in

the blood and to keep the body supplied with fuel to produce and maintain stores of energy.

Pancreatic Hormones• Insulin (beta cells)

– stimulates the uptake of glucose by body cells thereby decreasing blood levels of glucose  

• Glucagon (alpha cells)– stimulates the breakdown of glycogen and the release of glucose, thereby

increasing blood levels of glucose

• Glucagon and insulin work together to regulate & maintain blood sugar levels

• Glycogen – Polysaccharide consisting of numerous monosaccharide glucoses linked

together. Stored as an energy source in liver & muscles

EFFECTS OF INSULIN

Regulation of Blood Sugar

High blood sugarHigh blood sugar Insulin

Pancreas Glycogen Glucose

Decreased

Glycogen synthase

IncreasedIncreased

Hormone

Signal TransductionSignal Transduction

Blood

LiverLiver

Low blood sugar Glucagon

GTP-protein-linked receptor

Tyrosine-kinase-linked receptor

Glycogen phosphorylase

Cori & Cori (1947)

Juang RH (2004) BCbasics

CONTIN…….– Type One Diabetes (10-15%)

• results when the body’s immune system destroys its own beta cells in the pancreas. No insulin production is then possible.

– Type Two Diabetes (85-90%)results from either

• Insulin resistance (overweight people)• Inadequate insulin production (lean people)• A combination of both

• Gestational Diabetes

Diabetes diagnosed during pregnancy Increased health risk to mother and babyMay require insulin injectionsGoes away after birth, but increased risk of developing Type 2 DM for mother and child

Diabetes diagnosed during pregnancy Increased health risk to mother and babyMay require insulin injectionsGoes away after birth, but increased risk of developing Type 2 DM for mother and child

Pathophysiology of type 1 diabetes

Pathophysiology of type 2 diabetes

Type Two Diabetes• Usually over 40 yrs of age though the age of diagnosis is

getting younger• Gradual onset with mild symptoms • Most produce a normal amount of insulin but it is unable to

work properly due to insulin resistance• Many have complications at diagnosis

What is Insulin Resistance?

• condition in which the body does not utilise insulin efficiently

• Insulin resistance is the decreased response of the liver and peripheral tissues (muscle, fat) to insulin– Insulin resistance is a primary defect in the

majority of patients with Type 2 diabetes

Insulin resistance syndrome(syndrome x,metabolic syndrome,REAVEN’S SYNDROME)• Metabolic syndrome is a name for a group of risk factors that occur

together and increase the risk for CAD, STROKE, and type 2 diabetes • The two most important risk factors for metabolic syndrome are: • Extra weight around the middle and upper parts of the body (central

obesity). The body may be described as "apple-shaped."• Insulin resistance, in which the body cannot use insulin effectively. Insulin

is needed to help control the amount of sugar in the body. As a result, blood sugar and fat levels rise.

• Other risk factors include:• Aging• Genes that make more likely to develop this condition • Hormone changes• Lack of exercise

• metabolic syndrome is present if ONE have three or more of the following signs:

• Blood pressure equal to or higher than 130/85 mmHg• Fasting blood sugar (glucose) equal to or higher than 100

mg/dL• Large waist circumference (length around the waist):

– Men - 40 inches or more– Women - 35 inches or more

• Low HDL cholesterol: – Men - under 40 mg/dL– Women - under 50 mg/dL

• Triglycerides equal to or higher than 150 mg/dL

• Tests that may be done to diagnose metabolic syndrome include:

• Blood pressure measurement• Glucose test• HDL cholesterol level• LDL cholesterol level• Total cholesterol level• Triglyceride level

Type 2 Diabetes Risk Factors• Increasing age• Obesity – especially abdominal

– Women with BMI > 35 compared to 22 have a 93 fold increased risk

– Men with BMI > 35 have 40 fold increased risk• Physical inactivity• Family history• Ethnic background• High blood pressure• High Cholesterol• Previous gestational diabetes

Characteristics of DiabetesType 1 Type 2• Usually under 30• Rapid onset• Normal or underweight• Little or no insulin • Ketosis common• Make up 15% of cases• Autoimmune plus environmental

factors• Low familial factor• Treated with insulin, diet and

exercise

• Usually over 40• Gradual onset • 80% are overweight• Most have insulin resistance• Ketosis rare• 85% of diagnosed cases• Part of metabolic insulin

resistance syndrome• Strongly hereditary• Diet & exercise, progressing to

tablets, then insulin

CLINICAL FEATURES OF DM

• Diabetes Mellitus Type 1

Clinical Manifestations:Polyuria – increased urinePolydipsia – increased thirstPolyphagia – increased hunger

3 ‘Ps”Weight lossFatigue Nausea, vomiting

Ketoacidosis may be a presenting sign

Clinical Manifestations:Polyuria – increased urinePolydipsia – increased thirstPolyphagia – increased hunger

3 ‘Ps”Weight lossFatigue Nausea, vomiting

Ketoacidosis may be a presenting sign

Diabetes Mellitus Type 1• Usually develop symptoms over a short period of time, and

the condition is often diagnosed in an emergency setting• In addition to high glucose levels, acutely ill

type 1 diabetics have high levels of ketones.– As cells cannot get glucose, they burn fats as an

alternate energy source– Ketones are produced by the breakdown of fat and

muscle, and are toxic at high levels– Ketones in the blood cause a condition called "acidosis”

or “ketoacidosis" (low blood pH)– Urine testing detects ketones in the urine– Blood glucose levels are also high.

Diabetes Mellitus Type 2

• Type 2 Clinical Manifestations:– Polydipsia – increased thirst– Polyuria – increased urine– Polyphagia – increased hunger– Fatigue– Blurred vision– Slow healing infections– Impotence in men

INVESTIGATION AND LABORATORY FINDINGS• URINALYSIS• BLOOD TESTING PROCEDURES• LIPOPROTEIN ABNORMALITIES IN DIABETES

URINALYSIS

• Urine glucose• Ketones• Protein(microalbuminia)

Blood tests

BLOOD GLUCOSEGLYCELATED HAEMOGLOBIN (HBA1C)BLOOD LIPIDS(TOTAL

CHOLESTROL,LDL,HDL,TRIGLYCERIDE)

Other test

• Routine blood count and coagulation screen• Arterial blood gases an any emergency like

diabetic ketoacidosis• Serum electrolyte and urea-creatinine• Lipid profile • Liver function test • Chest x ray• ECG

DIAGNOSTIC CRITERIA FOR DM

• Blood glucose levels - venous samples

• 1 sample is diagnostic if symptoms are present; 2 samples if asymtomatic:

– Fasting plasma glucose of > 7.0mmols(126MG/DL)

– Random plasma glucose of > 11.1mmols ( 200MG/DL)

– Plasma glucose of > 11.1(mmols (200MG/DL)2 hours after an oral glucose tolerance test (OGTT

GTT

• Venous Plasma • Fasting >126MG/DL DIABETES• Fasting 110MG/DL TO< 126MG/DL Impaired

Fasting Glycaemia• 2 hour level > 200MG/DL DIABETES• 2 hour 140MG/DL –200MG/DL Impaired

Glucose Tolerance

Impaired Fasting Glucose (IFG)

• Fasting plasma glucose > (100MG/DL)and (120) mmol/l

• Intermediate state between normal glucose tolerance and diabetes

• Present in 5% of the population and increasing with age

• Has greater risk CVD

Impaired Glucose Tolerance (IGT)• Fasting plasma glucose < 126MG/DLand OGTT 2 hour

value >140MG/DL but <200MG/DL• Intermediate state between normal glucose

tolerance and diabetes• Individuals often manifest hyperglycaemia only when

challenged with oral glucose in an OGTT• 2-5% of people with IGT progress to diabetes per

year• IGT associated with increase risk of developing

cardiovascular disease

MANAGEMENT OF DMMANAGEMENT OF DM

Cornerstones of Diabetes Management• Healthy eating• Exercise• Monitoring• Medication/Insulin• Health Care Team

Management of Diabetes

• Type One: Insulin + Healthy Eating + Exercise

• Type Two:• Healthy eating + exercise• then Healthy eating + exercise + tablets• then Healthy eating + exercise + tablets +

insulin

Diabetes MellitusDiabetes MellitusRole of Diet in Diabetic ManagementA. Goals for diabetic therapy include• 1. Maintain as near-normal blood glucose

levels as possible with balance of food with medications

• 2. Obtain optimal serum lipid levels• 3. Provide adequate calories to attain or

maintain reasonable weight

Diabetes MellitusB. Diet Composition• 1. Carbohydrates: 60 – 70% of daily diet

– Carbohydrates convert quickly to sugars• Advice patient to consume a similar amount of carbs at each

meal• Medications can work on a consistent glucose response from

foods

• 2. Protein: 15 – 20% of daily diet• 3. Fats: No more than 10% of total calories from

saturated fats

Diabetes Mellitus• 4. Fiber: 20 to 35 grams/day; promotes

intestinal motility and gives feeling of fullness• 5. Sodium: recommended intake 1000 mg per

1000 kcal• 6. Sweeteners approved by FDA instead of

refined sugars• 7. Limited use of alcohol: potential

hypoglycemic effect of insulin and oral hypoglycemics

Exercise & Weight Loss

• Benefits of a 10kg weight loss– Fall of 50% in fasting glucose– Fall of 10% total cholesterol– Fall of 15% LDL– Fall of 30% triglycerides– Rise of 8% HDL– Fall of 10 mmHg systolic, 20 mmHg

diastolic

SIGN guidelines

Oral HypoglycemicsOral Hypoglycemics

Oral Hypoglycemics All taken orally in the form of tablets.

Pts with type 2 diabetes have two physiological defects:

1. Abnormal insulin secretion2. Resistance to insulin action in target tissues

associated with decreased number of insulin receptors

Oral Anti-Diabetic Agents

SulfonylureasSulfonylureas Drugs other than Drugs other than

SulfonylureaSulfonylurea

Sulfonylureas (Oral Hypoglycemic drugs)Sulfonylureas (Oral Hypoglycemic drugs)

TolbutamideTolbutamide AcetohexamideAcetohexamide

TolazamideTolazamide

ChlorpropamideChlorpropamide GlipizideGlipizideGlyburideGlyburide

(Glibenclamide)(Glibenclamide)

GlimepirideGlimepiride

ShortShort

actingacting

First generationFirst generation

IntermediateIntermediate

actingacting

LongLong

actingacting

LongLong

actingacting

ShortShort

actingacting

Second generationSecond generation

Tolbutamid short-acting

Acetohexamideintermediate-

acting

Tolazamide intermediate-

acting

Chlorpropamide long- acting

Absorption Well Well Slow Well

Metabolism Yes Yes Yes Yes

Metabolites Inactive* Active +++ ** Active ++ ** Inactive **

Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs

Duration of action

Short (6 – 8 hrs)

Intermediate (12 – 20 hrs)

Intermediate (12 – 18 hrs)

Long( 20 – 60 hrs)

Excretion Urine Urine Urine Urine

FIRST GENERATION SULPHONYLUREA COMPOUNDS

* Good for pts with renal impairment Good for pts with renal impairment

** Pts with renal impairment can expect long t1/2

GlipizideShort- acting

Glibenclamide(Glyburide)Long-acting

GlimepirideLong-acting

Absorption Well Well WellMetabolism Yes Yes YesMetabolites Inactive Inactive InactiveHalf-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrsDuration of action

10 – 16 hrs 12 – 24 hrs 12 – 24 hrs

Excretion Urine Urine Urine

SECOND GENERATION SULPHONYLUREA COMPOUNDS

MECHANISM OF ACTION OF SULPHONYLUREAS

1) Release of insulin from β-cells

2) Reduction of serum glucagon concentration

3) Potentiation of insulin action on target tissues

SIDE EFFECTS OF SULPHONYLUREAS

1) Nausea, vomiting, abdominal pain, diarrhea

2) Hypoglycaemia

3) Dilutional hyponatraemia & water intoxication (Chlorpropamide)

4) Weight gain

CONTRAINDICATIONS OF SULPHONYLUREAS

1) Type 1 DM ( insulin dependent)

2) Parenchymal disease of the liver or kidney

3) Pregnancy, lactation

4) Major stress

Drugs other than Sulfonylurea Drugs other than Sulfonylurea

MetforminMetformin

BiguanidesBiguanides α-Glucosidaseα-Glucosidase

InhibitorsInhibitors

ThiazolidinedionesThiazolidinediones

AcarboseAcarbose RosiglitazoneRosiglitazone

PioglitazonePioglitazone

RepaglinideRepaglinide

NateglinideNateglinide

MeglitinidesMeglitinides

MEGLITINIDES

e.g. Repaglinide, Nateglinide

PHARMACOKINETICS

Taken orally

Rapidly absorbed ( Peak approx. 1hr )

Metabolized by liver

t1/2 = 1 hr

Duration of action 4-5 hr

MEGLITINIDES (Contd.)

MECHANISM OF ACTION

Bind to the same KATP Channel

as do Sulfonylureas,

to cause insulin release from β-cells.

MEGLITINIDES (Contd.)

CLINICAL USE

Approved as monotherapy and in combination with metformin in type 2 diabetes

Taken before each meal, 3 times / day

Does not offer any advantage over sulfonylureas;

Advantage: Pts. allergic to sulfur or sulfonylurea

SIDE EFFECTS:

Hypoglycemia

Wt gain ( less than SUs )

Caution in pts with renal & hepatic impairement.

BIGUANIDES e.g. Metformin

PHARMACOKINETICS

Given orally

Not bind to plasma proteins

Not metabolized

Excreted unchanged in urine

t 1/2 2 hr

BIGUANIDES (Contd.)

MECHANISM OF ACTION

1. Increase peripheral glucose utilization

2. Inhibits gluconeogenesis

3. Impaired absorption of glucose from the gut

Advantages of Metformin over SUs

Does not cause hypoglycemia Does not result in wt gain ( Ideal for obese pts )

BIGUANIDES (Contd.)

SIDE EFFECTS

1. Metallic taste in the mouth

2. Gastrointestinal (anorexia, nausea, vomiting,

diarrhea, abdominal discomfort)

3. Vitamin B 12 deficiency (prolonged use)

4. Lactic acidosis ( rare – 01/ 30,000-exclusive in

renal & hepatic failure)

1. Hepatic impairment

2. Renal impairment

3. Alcoholism

4. Heart failure

BIGUANIDES (Contd.)

CONTRAINDICATIONS

1. Obese patients with type 11 diabetes

2. Alone or in combination with sulfonylureas

BIGUANIDES (Contd.)

INDICATIONS

α-GLUCOSIDASE INHIBITORS

e.g. Acarbose

PHARMACOKINETICS

Given orally

Not absorbed from intestine except small amount

t1/2 3 - 7 hr

Excreted with stool

MECHANISM OF ACTION

Inhibits intestinal alpha-glucosidases and

delays carbohydrate absorption, reducing postprandial increase in blood glucose

α-GLUCOSIDASE INHIBITORS(Contd.)

SIDE EFFECTS

Flatulence

Loose stool or diarrhea

Abdominal pain

Alone does not cause hypoglycemia

α-GLUCOSIDASE INHIBITORS(Contd.)

INDICATIONS

Patients with Type 11 inadequately controlled by diet with or without other agents( SU, Metformin)

Can be combined with insulin

may be helpful in obese Type 11 patients (similar to metformin)

α-GLUCOSIDASE INHIBITORS(Contd.)

THIAZOLIDINEDIONE DERIVATIVES

New class of oral antidiabetics

e.g.: Rosiglitazone

Pioglitazone

PHARMACOKINETICS

- 99% absorbed

- Metabolized by liver

- 99% of drug binds to plasma proteins

- Half-life 3 – 4 h

- Eliminated via the urine 64% and feces 23%

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

MECHANISM OF ACTION

- Increase target tissue sensitivity to insulin by: reducing hepatic glucose output & increase

glucose uptake & oxidation in muscles & adipose tissues.

They do not cause hypoglycemia (similar to metformin and acarbose ) .

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

ADVERSE EFFECTS

- Mild to moderate edema

- Wt gain

- Headache

- Myalgia

- Hepatotoxicity

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

INDICATIONS

Type 11 diabetes alone or in combination with

metformin or sulfonylurea or insulin in patients

resistant to insulin treatment.

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

DPP-4 Inhibitor• Inhibits the dipeptidyl-peptidase 4 enzyme• Enhances the incretin hormones• GLP-1 (Glucagon-like peptide 1)• GIP (glucose-dependent insulinotropic

polypeptide)

Incretin HormonesStimulate insulin response from Stimulate insulin response from beta cells in a glucose-dependent mannerbeta cells in a glucose-dependent manner

Inhibit gastric emptyingInhibit gastric emptying

Reduces food intake and body weightReduces food intake and body weight

Inhibit glucagon secretion from Inhibit glucagon secretion from alpha cells in a glucose-dependent manneralpha cells in a glucose-dependent manner

DPP-4 Inhibitor• Available product: Januvia (Sitagliptin)• Once daily dosing• Indicated for use with metformin or

thiazolidinedione• Dosing adjustment for renal impairment• Adverse effects: Diarrhea, upper respiratory infection• Expensive

INSULIN THERAPHYINSULIN THERAPHY

Diabetes MellitusDiabetes MellitusMedications

A. Insulin• 1. Sources: standard practice is use of human insulin prepared by

alteration of pork insulin or recombinant DNA therapy2. Clients who need insulin as therapy:• a. All type 1 diabetics since their bodies essentially no longer

produce insulin• b. Some Type 2 diabetics, if oral medications are not adequate for

control (both oral medications and insulin may be needed)• c. Diabetics enduring stressor situations such as surgery,

corticosteroid therapy, infections, treatment for DKA • d. Women with gestational diabetes who are not adequately

controlled with diet • e. Some clients receiving high caloric feedings including tube

feedings or parenteral nutrition

• Insulin Degradation• Hydrolysis of the disulfide linkage between A&B

chains.• 60% liver, 40% kidney(endogenous insulin)• 60% kidney,40% liver (exogenous insulin)• Half-Life 5-7min (endogenous insulin) Delayed-release form( injected one)• Category B ( not teratogenic)• Usual places for injection: upper arm, front& side

parts of the thighs& the abdomen.• Not to inject in the same place ( rotate)• Should be stored in refrigerator& warm up to

room temp before use.• Must be used within 30 days.

TYPES OF INSULIN PREPARATIONS

1. Ultra-short-acting

2. Short-acting (Regular)

3. Intermediate-acting

4. Long-acting

3. Intermediate - acting insulins

e.g. isophane (NPH)

Turbid suspension

Injected S.C.(Only)

Onset of action 1 - 2 hr

Peak serum level 5 - 7 hr

Duration of action 13 - 18 hr

Insulin mixtures

75/25 70/30 50/50 ( NPH / Regular )

3. Intermediate - acting insulins (contd.)

Lente insulin

Turbid suspension

Mixture of 30% semilente insulin

70% ultralente insulin

Injected S.C. (only)

Onset of action 1 - 3 hr

Peak serum level 4 - 8 hr

Duration of action 13 - 20 hr

3. Intermediate - acting insulins (contd.)

Lente and NPH insulins

Are roughly equivalent in biological effects.

They are usually given once or twice a day.

N.B: They are not used during emergencies

(e.g. diabetic ketoacidosis).

4. Long – acting insulins e.g.Insulin glargine

Onset of action 2 hr

Absorbed less rapidly than NPH&Lente insulins.

Duration of action upto 24 hr

Designed to overcome the deficiencies of intermediate acting insulins

Advantages over intermediate-acting insulins:Constant circulating insulin over 24hr with no pronounced peak.

More safe than NPH&Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia).

Clear solution that does not require resuspention before administration.

Methods of Adminisration• Insulin Syringes• Pre-filled insulin pens• External insulin pump

Under Clinical Trials• Oral tablets• Inhaled aerosol• Intranasal, Transdermal • Insulin Jet injectors• Ultrasound pulses

COMPLICATIONS OF INSULIN THERAPY

1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening

Overdose of insulin

Excessive (unusual) physical exercise

A meal is missed

2. Weight gain

3. Local or systemic allergic reactions (rare)

4. Lipodystrophy at injection sites

5. Insulin resistance

6. Hypokalemia