Diabetes Mellitus and Metabolic Syndrome

DIABETES MELLITUS AND METABOLIC SYNDROME

PATHOPHYSIOLOGY:

Insulin is secreted by β-cells (also called B-cells) of the islets of Langerhans

In type 1 diabetes there is an absolute deficiency of insulin (such patients are usually young and non-obese at presentation)

In type 2 diabetes there is a relative lack of insulin secretion, coupled with marked resistance to its action (such patients are usually middle-aged or older and obese at presentation)

DIAGNOSIS:

Normal fasting blood glucose: 70- 99 mg/dl ( 3,9-5,5 mmol/l)

Criteria for hypoglycemia: < 70 mg/dl,regardless of the clinical symptoms

CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUS:

Symptoms of diabetes plus random blood glucose concentration >=200 mg/dl ( 11,1 mmol/L) or

Fasting plasma glucose >=126 mg/dl ( 7,0 mmol/L)- double confirmationor

2-h plasma glucose>=200 mg/dl ( 11,1 mmol/L) during an oral glucose tolerance test

ORAL ANTIDIABETIC AGENTS:

Biguanides (metformin)

Sulphonylureas

Thiazolidinediones (glitazones)

 α-glucosidaseinhibitors (acarbose)

Incretin mimetics ( GLP-1 receptor agonists, DPP-4 inhibitors)

SGLT-2 inhibitors

BIGUANIDES: METFORMIN

It is used in type 2 diabetic patients inadequately controlled by diet

Biguanides are recommended as first-line therapy for type 2 diabetes (recommended especially in obese patients)

Metformin does not increase body weight or provoke hypoglycemia

Primaryeffectis to:

 reduce hepatic glucose production through activation of the enzyme AMP-activated protein kinase (AMPK)

impairment of renalgluconeogenesis,

slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes,

direct stimulation of glycolysis in tissues,

increasedglucoseremoval from blood

reduction of plasmaglucagonlevels

Hypoglycemia during metformin therapy is essentially unknown

METFORMIN-ADVERSE EFFECTS:

Metformincauses nausea, a metallic taste, anorexia, vomiting and diarrhoea

Lactic acidosis, which has a reported mortality in excess of 60%, is uncommon provided that the above contraindications are respected

METFORMIN- CONTRAINDICATIONS:

Renal disease ( GFR< 30 ml/min/1,73m2- do not use, GFR 30-44 ml/min/1,73 m2- do not start therapy, you can continue but the dose should be reduced >50%, renal function should be monitored every 3 months

Liverdisease

Advanced heart failure, stroke, myocardial infarction

Radiographiccontraststudies

Acidosis

THE DOSAGE OF METFORMIN

SULPHONYLUREAS-MECHANISM OF ACTION:

The major action of sulfonylureas is to increase insulin release from the pancreas and reduction of serum glucagon concentrations

Sulphonylureas (e.g. glibenclamide, gliclazide) are used for type 2 diabetics who have not responded adequately to diet alone or diet and metformin

They improve symptoms of polyuria and polydipsia, but (in contrast to metformin) stimulate appetite

SULPHONYLUREAS-ADVERSE EFFECTS:

Sulphonylureascancausehypoglycaemia

Allergic reactions to sulphonylureas include rashes, drug fever, gastrointestinal upsets, transient jaundice (usually cholestatic) and haematopoietic changes, including thrombocytopenia, neutropenia and pancytopenia

Serious effects other than hypoglycaemia are uncommon

Contraindications: Renal/liverdisease

THE DOSAGE OF SULPHONYLUREAS

THIAZOLIDINEDIONES (GLITAZONES):

Glitazones lower blood glucose and haemoglobin A1c (HbA1c) in type 2 diabetes mellitus patients who are inadequately controlled on diet alone or diet and other oral hypoglycaemic drugs

Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a nuclear receptor found mainly in adipocytes and also in hepatocytes and myocytes

They lower blood sugar but cause weight gain and fluid retention

They are contraindicated in heart failure

ALPHA-GLUCOSIDASE INHIBITORS-ACARBOSE:

Acarbose is used in type 2 diabetes mellitus in patients who are inadequately controlled on diet alone or diet and other oral hypoglycaemic agents

It can be used in combination with insulin or metformin and sulphonylureas

Acarboseis a reversible competitive inhibitor of intestinal α-glucoside hydrolases and reduce postmeal glucose excursions by delaying the digestion and absorption of starch and disaccharides

ACARBOSE- ADVERSE EFFECTS:

Fermentation of unabsorbed carbohydrate in the intestine leads to:

Abdominalorstomachpain

Bloated feeling or passing of gas

Diarrhea

Contraindications to Acarbose are:Renal and liver impairment, bowel or intestinal disorder, a stomach disorder

THE DOSAGE OF ACARBOSE

GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS:

Mechanism of action:

potentiation of glucosemediated insulin secretion,

suppression of postprandialglucagon

slowed gastric emptying, and a central loss of appetite (weight loss)

Exenatide (Byetta )and Liraglutide (Victoza)

GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, ADVERSE EFFECTS:

nausea, vomiting, diarrhea

allergicreaction

CONTRAINDICATIONS:Renaldisease

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS:

Sitagliptin, saxagliptin, and linagliptinare inhibitors of DPP-4, the enzyme that degrades incretin hormones

These drugs increase circulating levels of native GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), which ultimately decrease postprandial glucose excursions by increasing glucose-mediated insulin secretion and decreasing glucagon levels

Dosage should be reduced in patients with renalimpairment and may need to be adjusted to prevent hypoglycemia if there is concurrent insulin secretagogue or insulin therapy

ADVERSE EFFECTS:

• nausea and vomiting
• skin reaction ( e.g hives)
• epigastricpain

Reduced dose with renal disease

SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS:

Mechanism of action: ↑ Urinary glucose excretion

Clinicaluse:

Monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance;

Add-on combination therapy in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control

ADVERSE EFFECTS:

urinary and vaginal infections, dehydration, an exacerbate tendency to hyperkalemia

Contraindications:moderaterenalinsufficiency

Dapagliflozin , Canagliflozin

INSULIN-CHARACTERISTICS OF AVAILABLE INSULIN PREPARATIONS:

RAPID-ACTING INSULINanalog:

insulin lispro- Humalog

insulin aspart- NovoRapid

insulin glulisine- Apidra

The rapid-acting insulin permit more physiologic prandial insulin replacement because their rapid onset and an early peak action mimic normal endogenous prandial insulin secretion more closely than regular insulin does, and they have the additional benefit of allowing insulin to be taken immediately before the meal

Their duration of action is rarely more than 4–5 hours, which decreases the risk of late postmeal hypoglycemia

SHORT-ACTING INSULIN:

Its effect appears within 30 minutes, peaks between 2 and 3 hours after subcutaneous injection, and generally lasts 5–8 hours

Human insulin, short-acting: Actrapid, Gensulin R, Humulin R, Insuman Rapid , Polhumin R

Regular insulin should be injected 30–45 or more minutes before the meal

INTERMEDIATE-ACTING NPH (ISOPHANE INSULIN)

NPH insulin is an intermediate-acting insulin whose absorption and onset of action are delayed by combining appropriate amounts of insulin and protamine so that neither is present in an uncomplexed form (“isophane”)

After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin

NPH insulin has an onset of approximately 2–5 hours and duration of 4–12 hours

It is usually mixed with regular, lispro, aspart, or glulisine insulin and given two times daily

LONG-ACTING INSULIN, INSULIN GLARGINE:

Insulin glargine is a soluble, “peakless” long-acting insulin analog

Insulin glargine has a slow onset of action (1–1.5 hours) and achieves a maximum effect after 4–6 hours

This maximum activity is maintained for 11–24 hours or longer

Glargine is usually given once daily, although some very insulin-sensitive or insulin-resistant individuals benefit from split (twice a day) dosing

LONG-ACTING INSULIN, INSULIN DETEMIR:

Insulin detemir has a dose-dependent onset of action of 1–2 hours and duration of action of more than 12 hours

It is given once or twice a day to obtain a smooth background insulin level

MIXTURES OF INSULIN

TYPE 2 DIABETES MELLITUS-TREATMENT:

Pharmacological treatment- STEP 1:

lifestylemodification + Metformin

-metformin intolerance or contraindication ( Sulphonylureas or Dipeptidyl peptidase-4 (DPP-4) inhibitors or Sodium-glucose cotransporter 2 inhibitors or Pioglitazone)

Pharmacological treatment- STEP 2 (dual therapy) :

lifestylemodification + Metformin +

-Sulphonylureas or

-Glucagon-like polypeptide-1 (GLP-1) receptor agonists or

-Dipeptidyl peptidase-4 (DPP-4) inhibitors or

-Sodium-glucose cotransporter 2 inhibitors ( SGLT-2) or

- Pioglitazone

Pharmacological treatment- STEP 2 (triple therapy)

lifestyle modification + Metformin + two different drugs with different mechanisms of action

It is also possible to add Basal Insulin to Metformin (a direct transition from STEP 1 to STEP 3)

Pharmacological treatment- STEP 3:

lifestyle modification+ Metformin+ Insulin (Basal insulin): NPH 1x/daily or Long-acting analog

Pharmacological treatment- STEP 4:

lifestyle modification+ Metformin+ Insulin in two doses ( Basal insulin or Mixtures of insulin)

lifestyle modification + Metformin+ intensive insulin therapy

There is a possibility of adding to insulin other antidiabetic drugs(besides metformin)

THE CRITERIA FOR STARTING INSULIN TREATMENT IN TYPE 2 DIABETES:

newlydiagnoseddiabetes:

-glucose ≥ 300 mg / dl (16.7 mmol / l) with clinical symptoms of hyperglycemia;

the ineffectiveness of oral diabetic medications (HbA1c> 7%, despite the intensification of behavioral therapy)

INDICATIONS TO INSULIN TREATMENT (INDEPENDENT OF THE CONCENTRATION OF GLUCOSE):

pregnancy

the patient'srequest

latentautoimmunediabetes in adults

diabetesassociated with cysticfibrosis

INDICATIONS FOR TEMPORARY INSULIN THERAPY:

surgery , stroke , acute coronary syndrome , percutaneous transluminal coronary angioplasty , decompensation of diabetes (e.g caused by infection, injury, steroid therapy) , other acute illness requiring hospitalization in Intensive Care Unit

THE METABOLIC SYNDROME:

CRITERIA FOR THE METABOLIC SYNDROME:

Three or more of the following:

Central obesity: waist circumference>=94 cm(men), >= 80cm ( female)

Hypertriglyceridemia: triglyceride level >=150 mg/dL or specific medication

Low HDLcholesterol: <40 mg/dL for men and <50 mg/dL for women, respectively, or specific medication

Hypertension: blood pressure ≥130 mmHg systolic or
≥85 mmHg diastolic or specific medication

Fasting plasma glucose level ≥100 mg/dL or specific medication or previously diagnosed type 2 diabetes

THE METABOLIC SYNDROME- TREATMENT:

All componentsof metabolic syndromeshould betreated: obesity (weight reduction is the primary approach to the disorder, recommendations for weight loss include a combination of caloric restriction, increased physical activity, and behavior modification)insulin resistance( metformin) dyslipidaemia (statins, fibrate), hypertension.