DIABETES MELLITUS


As promised in my last post on insulin, I’m here with this post on diabetes mellitus.

So basically, diabetes is an endocrine disorder characterised with high blood sugar levels.

As we know, insulin plays an important role in regulating glucose metabolism; any alteration in insulin production or sensitivity of insulin receptors on our body cells will cause diabetes.

Now based on the defect, diabetes mellitus is broadly categorised into-

Type – I DM:  Pancreas's failure to produce enough insulin due to loss of beta cells

                                                                                                                            

Type – II DM: Insulin resistance This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes".

 

Gestational diabetes: Occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.


In this post we will mainly discuss on the pharmacological (treatment) aspect of diabetes mellitus. Before that, let's look into the normal blood sugar levels:

What are the normal blood sugar levels? - Quora

As discussed in the earlier post, for type I diabetes mellitus, insulin therapy shall suffice.

However, one limitation of insulin is that it needs to be given by injection. So, oral antidiabtetic drugs have been prepared.

Here is the classification of oral hypoglycaemic drugs:





PATHOGENESIS OF DM-II



Now we'll look into each category one by one…

INSULIN RELEASE ENHANCERS

The K- ATP channel blockers basically increase insulin release by depolarisation of the beta cells.

SULFONYLUREAS

They bind to their specific receptors (SUR-1) present on the outer surface of the K+ ATPase channels in our beta cells of the pancreas. This causes closure of the K+ channels and thus causes depolarisation of the cell. This in turn leads to Ca++ influx and brisk exocytosis of insulin granules.

This group of drugs is mainly implicated for type- II DM. As these drugs are metabolised in liver and excreted by kidney, they are contraindicated in liver and kidney failure.

1st generation SUs:

·       Acetohexamide

·       Chlorpropamide (causes adverse effects like SIADH, cholestatic jaundice, Disulfiram like reaction)

·       Tolbutamide- Is hepatotoxic

     (Due to these adverse effects and more efficacious 2nd gen. SUs, these are not preferred these days)

2nd generation SUs:

·       Glibenclamide

·       Glipizide

·       Gliclazide

·       Glimepiride

-These are the currently used SUs, have been selected over 1st generation SUs.

-After a few months of administration, insulinaemic action declines due to down- regulation of receptors. However glucose tolerance is maintained and in this phase, target tissues like liver are sensitised to insulin action. Long term use however re-establishes insulin receptors.

Though incidence of adverse effects is quite low, the following must be kept in mind-

·       Hypoglycaemia: Mainly in elderly patients having liver or kidney diseases. Hypoglycemic risk is lower with 2nd generation drugs.

·       Weight gain (1-3 kg)

·       Hypersensitivity

 

MEGLITINIDE- Phenylalanine analogues

These are quick and short lasting insulinaemic drugs used for postprandial hyperglycemias in type-II diabetes mellitus. These also have lesser hypoglycaemic and weight gain like adverse effects than SUs.

1.        Rapaglinide- like SUs these act in an analogous manner i.e.-


However, because of its fast acting and short lasting action, it is used in a different pattern from SUs. It controls post prandial hyperglycemias and hence must be omitted if a meal is skipped.

·       Side effects include- headache, arthralgia and dyspepsia.

·       It is contraindicated in patients with liver disease.

2. Nateglinide- Principally stimulates the first phase insulin release. It has a faster onset and shorter lasting than rapaglinide. Episodes of hypoglycaemia are lesser. Side effects are similar to rapaglinide; it may cause nausea and flu like symptoms too.

 

DIPEPTIDYL  PEPTIDASE-4 (DPP-4)  INHIBITORS

If you look into the figure given above showing the mechanism of action of insulin secretion enhancers, you will find that incretins like GLP-1 (Glucagon like peptide-1), GIP etc. activate cAMP pathways and cause exocytic release of insulin granules. The enzyme DPP-4 metabolises these incretins and decreases its availability. Thus, inhibiting this enzyme contributes towards insulin secretion.

The drugs included are-

1.   Sitagliptin- It competitively inhibits DPP-4 and boosts insulin release, decreases glucagon release and lowers meal time as well as fasting blood glucose in Type-II diabetes. Also, it lowers HbA1c levels like metformin. Stronger HbA1c lowering is achieved when given with metformin, SUs or pioglitazone. Most regimens prefer sitagliptin as an adjuvant, however it can be used as a monotherapy too; for maintenance.

·       Side effects – headache, loose stools, pancreatitis, rashes, allergic reactions in few cases, nasopharyngitis.

·       Contraindications- renal failure

Other DPP-4 inhibitors are similar to sitagliptin-

2.      Vildagliptin

3.      Saxagliptin

4.      Teneligliptin

 

GLP-1 AGONISTS

     These drugs were found before DPP-4 antagonists, from the saliva of Gila monster (Exentin 4). It was found to have hypoglycemic properties. The drugs included are:

      Semisynthetic drugs:

·                 Exenatide

·                 Lixisenatide

      GLP-1 analogues:

·       Liraglutide

·       Abiglutide

·       Dulaglutide

·       Semaglutide

These are peptide drugs and hence are to be avoided by oral route; most of them are given subcutaneously. 

·       Side effects: pancreatitis, vomiting, nausea, weight loss.

·       Contraindications- renal failure, medullary carcinoma of thyroid.

 

 

OVERCOME INSULIN RESISTANCE

BIGUANIDE (AMPK activator)

Metformin

Metformin is a euglycemic drug rather than hypoglycaemic. One interesting thing about this is, it requires insulin for its action and hence cannot be given in pancreatectomised individuals. The image given below effectively explains the mechanism of action. AMPK (AMP dependent protein kinase) plays a crucial role.

1.      Mainly, Suppresses hepatic gluconeogenesis and glucose output from liver.

2.      Enhance insulin mediated glucose uptake in

3.      Interferes with mitochondrial respiratory chain and promotes anaerobic glycolysis (lactic acidosis).

·       Side effects- Abdominal pain, anorexia, bloating, nausea, metallic taste, mild Lactic acidosis, Vit-B-12 deficiency

·       Contraindications- renal failure, hypotensive cases, heart failure, alcoholics.

USES-

PPAR-Gamma AGONIST/ THIOZOLIDINEDIONE

Thiazolidinediones, also known as glitazones, are a group of oral anti-diabetic drugs.

Pioglitazone

Mechanism of action:

TZDs work by targeting the PPAR-gamma receptor, which activates a number of genes in the body and plays an important role in how the body metabolises glucose and how the body stores fat. TZDs can therefore help boost insulin sensitivity.

The benefits of glitazones include decreased blood glucose levels and preservation of the pancreas’s ability to produce sufficient levels of insulin. Glitazones also help lower blood pressure and improve lipid metabolism by increasing levels of HDL (or ‘good’) cholesterol and reducing levels of triglycerides – a type of fat in the bloodstream and fat tissue.

·       Side effects- fluid retention, weight gain, precipitation of CHF.

·       Contraindications- Pregnancy

 

 

INSULIN RELEASE ENHANCERS

ALPHA - GLUCOSIDASE INHIBITORS

Alpha-glucosidase inhibitors (AGIs- acarbose, miglitol, voglibose) are widely used in the treatment of patients with type 2 diabetes. AGIs delay the absorption of carbohydrates from the small intestine and thus have a lowering effect on postprandial blood glucose and insulin levels.

·       Side effects- flatulence, diarrhoea

·       Contraindications- diabetic keto acidosis, ulcerative colitis(IBD), liver failure.



MISCELLANEOUS DRUGS

DOPAMINE D2 AGONIST

Bromocriptine

SODIUM GLUCOSE COTRANSPORTER (SGLT-2) INHIBITOR

Dapagliflozin

Canagliflozin

BILE ACID SEQUESTRANT

Colesevelam



TREATMENT REGIMEN FOR DIABETES MELLITUS





RECENT ADVANCES

LATENT AUTOIMMUNE  DIABETES IN ADULTS (LADA)- DIABETES-TYPE-1.5

This is a condition that shares characteristics of both type-I and type II DM. the beta cells tend to get destroyed (as part of autoimmune reaction) much faster in this condition than in type-II. The condition not reversible with lifestyle changes. 
Causes:- Antibodies against insulin producing cells. In obese patients, insulin resistance may also be present.
This is often misdiagnosed as type-II diabetes. It is said that 10% of patients currently having type-II DM, are actually having type-1.5 DM.
People who have type 1.5 diabetes tend to meet the following criteria:
  • They’re not obese.
  • They’re over the age of 30 at the time of diagnosis.
  • They’ve been unable to manage their diabetes symptoms with oral medications or lifestyle and dietary changes.
Insulin treatment is the treatment of choice. Frequent monitoring of blood glucose levels is advised.


TYPE -3 DIABETES MELLITUS

This type of DM is referred to a condition where Alzheimer's disease (a major cause of dementia) is triggered by insulin resistance or insulin like growth factor resistance (IGF) dysfunction. (This is not to be confused with type-3c DM where exocrine pancreas insufficiency causes secondary endocrine insult). 

This type of Alzheimer is often referred to as ' Diabetes of the Brain'. The link between diabetes and Alzheimers is yet to be deciphered. In the brain, diabetes can cause inflammation of the blood vessels which further damages brain cells. According to Alzheimer's Association, the symptoms include:

  • memory loss that affects daily living and social interactions
  • difficulty completing familiar tasks
  • misplacing things often
  • decreased ability to make judgements based on information
  • sudden changes in personality or demeanor
Diagnosis include - neurological examination, medical history, neurophysiological testing.

Lifestyle changes, such as making changes to your diet and including exercise in your daily routine, may be a big part of treatment.

Here are some additional treatment tips:

  • If you’re living with overweight, try to lose your body mass. This can help stop organ damage caused by high blood sugar and may prevent the progression of pre-DM2 to DM2.
  • A diet low in fat and rich in fruits and vegetables can help improve symptoms.
  • If you smoke, quitting smoke is recommended because it can also help manage your condition.
  • If you have both type 2 diabetes and Alzheimer’s, treatment for your type 2 diabetes is important to help slow the progression of dementia.
  • Metformin and insulin are an anti-diabetes drugs.
  • Acetylcholinesterase inhibitors like donepezil (Aricept), galantamine (Razadyne), or rivastigmine (Exelon) can be prescribed to improve the way that your body’s cells communicate with one another.
  • Memantine (Namenda), an NMDA-receptor antagonist, may also help to reduce symptoms and slow the progression of Alzheimer’s disease.

Other symptoms of Alzheimer’s and other dementia types, like mood swings and depression, may be treated with psychotropic drugs. Antidepressants and anti-anxiety medications are part of treatment in some cases.

Some people may need a light dose of antipsychotic therapy later in the course of the dementia.