Diabetes Mellitus: Types, Diagnosis, and Treatment

• The lecture provides an overview of the pharmacology of Diabetes Mellitus
• The lecturer is Prof Steve Safrany 341
• These notes are for the Year 2 Endocrine and Breast module, January 2024

Learning Outcomes

• Describe the mechanism of action of insulin, and know its therapeutic and adverse effects
• Compare and contrast different types of insulin preparations & regimens used to treat diabetes, and know their advantages and disadvantages
• Discuss potential future directions for insulin therapy in diabetes mellitus, including new insulin formulations, devices, & technologies
• Recognise principles of pharmacotherapy of type 2 diabetes, including different classes of drugs, their mechanism of action, and adverse effects
• Evaluate the clinical efficacy of antidiabetic drugs, including their effects on glycemic control, weight, blood pressure, lipid profiles, and other outcomes

Diagnosis of Diabetes

• Diagnosis involves measuring plasma glucose levels
• Fasting plasma glucose of ≥7.0 mmol/L (126 mg/dL) indicates diabetes
• An HbA1c ≥48 mmol/mol (6.5%) indicates diabetes
• A two-hour plasma glucose ≥11.1 mmol/L (200 mg/dL) after a 75g oral glucose load (oral glucose tolerance test (OGTT)) indicates diabetes
• Random plasma glucose ≥11.1 mmol/L (200 mg/dL) in the presence of hyperglycaemia symptoms also indicates diabetes

Type 2 vs Type 1 Diabetes

Type 2 Diabetes

• There is insulin resistance with relative insulin deficiency
• Hyperglycemia develops gradually with progressive decline in beta-cell function, initially silent
• Patients can be treated with oral medications
• Onset is associated with increasing age and obesity

Type 1 Diabetes

• There is absolute insulin deficiency
• There is abrupt onset of hyperglycemia and propensity for development of DKA
• Insulin is required
• Auto antibodies are associated with Type 1
• Predominant type of diabetes is diagnosed in individuals <30 years old

Management of DM

Type 2 Diabetes

• A multidisciplinary approach that includes:
• Patient education & support is required
• Lifestyle modifications (diet, physical activity, & weight loss) is required
• Pharmacologic therapies (oral, GLP-1 agonists, insulin) are often needed
• Bariatric surgery can be considered

Type 1 Diabetes

• A multidisciplinary approach that includes
• Patient education & support
• Dietary advice (carb counting, glycaemic index diets, dietary advice) and physical activity advice
• Insulin therapy (injections or insulin pump)
• Newer treatments on the horizon (islet cell, stem cell)

Indications for Insulin

• Type 1 diabetes
• Inadequately controlled type 2 diabetes
• Temporary use in:
• Hospitalisation/surgery
• Pregnancy
• Renal disease (when there are limited options for oral medications)
• Initiating glycemic control in patients with severe new onset type 2 diabetes

Treatment of Type 1 Diabetes

• It involves insulin replacement therapy
• Adjust doses according to:
• Carbohydrate intake
• Exercise regimen
• Blood glucose profile
• Perform blood glucose tests and adjust insulin appropriately
• Monitor for complications

Bolus Insulin

• It is a rapid or short-acting insulin given before meals
• It provides coverage for food intake or correction of hyperglycemia

Short Acting Bolus Insulin

• Regular insulin

Rapid Acting Bolus Insulin

• Aspart
• Lispro
• Glulisine
• (Insulin human) inhalation powder

Basal Insulin

• It aims to mimic physiologic insulin secretion
• It maintains euglycemia in the fasting state

Intermediate Acting Basal Insulin

• NPH (Neutral Protamine Hagedorn), given once or twice daily

Long Acting Basal Insulin

• Glargine - once daily
• Detemir - once or twice daily
• Degludec - once daily

NPH – intermediate acting

• Neutral protamine Hagedorn
• Includes Humulin N, Novolin N, Novolin NPH, and isophane insulin
• Created in 1936 as first basal insulin
• A suspension of crystalline zinc insulin combined with the positively charged polypeptide, protamine*
• Has an intermediate duration of action (10-20 hours)
• It can be combined with other insulins
• A peak in action increases risk of hypoglycemia

Insulin Glargine – Basal Insulin

• It creates a peakless 24-hour insulin
• Insulin molecule modifications include:
• Substitution of glycine at A21
• Addition of two arginines at B30
• It has a unique release pattern at injection site

Pharmacodynamics of Insulin

• Aspart/lispro/glulisine has an onset of action of 5-15 min, peak in 1-2 hrs, and lasts for 4-6 hrs
• Regular insulin has an onset of action of 30-60 min, peaks in 2-4 hrs, and lasts for 6-10 hrs
• Human NPH has an onset of action of 1-2 hrs, peaks in 4-8 hrs, and lasts for 10-20 hrs
• Glargine has an onset of action of 1-2 hr, lasts ~24 hrs
• Detemir has an onset of action of 0.8-2 hr, lasts up to 24 hrs
• Degludec has an onset of action of 1 hr, lasting up to 42 hrs

Insulin Administration Regimens

Conventional

• Basal insulin only
• Twice daily mixed split
• Intermediate (N) + Short (Regular or Rapid acting)
• Includes 70/30 or 75/25 insulin
  • 70-75% N
  • 25-30% R or Rapid acting

Basal-Bolus

• Long-acting insulin + Rapid-acting insulin is taken with each meal

Insulin Pump

• Continuous subcutaneous insulin infusion can be administered via an insulin pump

Pitfalls of Conventional Twice-Daily Split-Mixed Regimen

• It results in endogenous insulin
• The timing of Dawn phenomenon, breakfast, dinner, and other timings are critical

Mimicking Nature: The Basal-Bolus Insulin Concept

• It is designed to mimic endogenous insulin to create a system that closely resembles natural insulin level fluctuation

Insulin Pump Therapy

• An insulin pump administers insulin through a catheter in the abdominal fat to help control a person's blood sugar levels

Pharmacokinetic Advantages of the Insulin Pump (CSII)

• It uses rapid-acting insulin
• It uses 1 injection site
• Basal insulin requirements supplied in mini-boluses every 5 minutes (Closed loop technology)

Automated Insulin Delivery Systems (Hybrid Closed Loop Device)

• It comprises an insulin pump and a continuous glucose monitor (CGM) with integrated functioning
• It enables automatic adjustment of insulin delivery
• An algorithm adjusts basal rates based on glucose
• A patient still needs to administer pre-meal insulin boluses
• Benefits include increased time spent in target glucose range and reduced incidences of severe hypoglycemia
• It has high costs

Inhaled Insulin

• Rapid-acting insulin adsorbed onto carrier particles
• It is delivered via inhalation
• The median time for maximum effect is 53 minutes
• The duration of action is 160 minutes
• Approved to cover prandial insulin requirements in non-smoking adults with DM with free of pulmonary disease
• It is rarely used – less effective than subcutaneous insulin and may be toxic for the pulmonary system

Insulin Side Effects

• It is a safe treatment when used appropriately
• Hypoglycemia is the most common complication
• Insulin Lipodystrophies can occur
• Lipoatrophy: Localised loss of subcutaneous fat at injection sites
• Lipohypertrophy: Swelling of subcutaneous fat at injection sites
• Allergies can occur
• Local: itching, burning, erythema, hive formation
• Systemic: urticaria/bronchospasm

Summary of Insulin Use

• Insulin is used in the treatment of both type 1 and type 2 diabetes
• Multiple daily injections (basal-bolus) are most commonly used
• Hypoglycemia is a common side effect of insulin therapy, so patient education is important
• A basal-bolus regimen via subcutaneous injections or continuous insulin infusion most closely simulate normal insulin physiology

Principles of Glucose Lowering Agents in Type 2 Diabetes

• Multiple drugs are available, each with tissue-specific action
• All are contraindicated in pregnancy except glyburide (sulfonylurea) and metformin
• Can be used in any combination except sulfonylureas should not be used with meglitinides
• Metformin is generally the first drug of choice
• One can start with multiple classes of drugs

Insulin Resistance

• Clinical conditions associated include:
• Hypertension (Prehypertension)
• Type 2 Diabetes
• Impaired Glucose Tolerance
• Atherosclerosis (Endothelial Dysfunction)
• Obesity (Central Visceral)
• Dyslipidemia
  • ↓HDL
  • ↑ LDL
  • ↑TG
• Polycystic Ovary Disease
• Decreased Fibrinolytic Activity
• Acanthosis Nigricans

Pathogenesis of Hyperglycaemia in T2D

• Insulin resistance: defects in insulin signaling prevent uptake by liver and peripheral tissues
• Increased glucose production
• Insufficient glucose disposal

Organs Regulating Plasma Glucose

• Pancreas
• Liver
• Muscles
• Gut
• Brain
• Kidneys

Metformin (Glucophage)

• Action:
• Acts on the liver (activates AMPK?)
• Reduces hepatic glucose output (i.e., reduces gluconeogenesis)
• Decreases glucose absorption in large intestine
• Increases insulin-mediated glucose utilisation in peripheral tissues
• Is associated with mild weight loss
• Does not cause hypoglycaemia
• Efficacy: can lower HbA1c as much as 2%
• Most commonly prescribed drug for T2D

Side Effects and Contraindications of Metformin

• Side effects*
• GI upset – anorexia, nausea, and diarrhoea (most common)
• Lactic Acidosis – rare, but a concern due to high-case fatality rate
• Vitamin B12 deficiency – due to reduction in intestinal absorption of B12 – rarely causes megaloblastic anaemia
• Contraindications
• Patients prone to metabolic acidosis
• T1D
• Renal failure
  • eGFR 30-45ml/min – lower dose
  • eGFR <30ml/min – avoid

Insulin Secretagogues: 1. Sulfonylureas

• Names include Glipizide, glimepiride, glyburide
• Action involves stimulating pancreatic insulin secretion for 12-24 hours
• Mechanism includes binding K+ channels/sulfonylurea receptors (SUR) in ẞ cells, resulting in K+ accumulation and depolarisation, causing Ca2+ entry and insulin release
• It has an immediate effect mostly on pre-meal glucose
• Hepatically metabolised, excreted via kidney with active metabolites so caution in renal impairment is required
• Contraindications include T1DM, DKA, sulfa allergy
• Adverse effects include hypoglycemia, weight gain, hunger
• Efficacy: Lowers A1c up to 1.5%

Meglitinides/glinides

• Name: repaglinide
• It stimulates insulin secretion for 3-4 hours
• Mechanism is same as sulfonylureas
• Results in a fast onset
• Side effects cause lower glucose 2-4 hours after meal, and weight gain
• Disadvantage involves reduced patient compliance
• Contraindications include T1DM, liver failure, DKA, sulfa allergy
• Metabolism: hepatic by CYP 450 enzymes system, 96% metabolites excreted via GI tract
• Efficacy: Lowers A1c ~ 1.4%

Alpha-glucosidase Inhibitors

• Name: acarbose
• Mechanism: competitive inhibition of enzymes in the small intestinal brush border to break down oligosaccharides and disaccharides into monosaccharides
• Action: delays gut carbohydrate absorption, increasing GLP-1
• Effects: only affects post-prandial glucose
• Administration: requires a pill taken with meals
• Side effects: flatulence, abdominal bloating
• Contraindications: GI disorders, esp. IBD
• Metabolism: renally excreted as unchanged drug
• Does not induce hypoglycemia
• Efficacy: lowers A1c ~ 0.4%

Incretin Hormones

• Released from gut after eating and enhance insulin secretion
• GLP-1 and GIP are the main incretin hormones responsible for this effect in healthy individuals
• In T2DM, the incretin effect is often impaired
• This impairment may contribute to poor glucose regulation and reduced insulin secretion from the pancreas in T2DM
• ↑ Glucose uptake by adipose and muscle tissue
• Blood glucose homeostasis

GLP-1

• Leads to increased insulin production and lowered Glucagon productio
• Slows Gut motility
• Induces Satiety

GLP-1 Receptor Agonists (GLP-1 RA)

• Names : Semaglutide, liraglutide, dulaglutide
• Mechanism: Enhancement of glucose-dependent insulin secretion, slowed gastric emptying, & reduction of postprandial glucagon & food intake
• Action is potent glucose-dependent insulin secretion, inhibits glucagon secretion, indirectly slows gastric emptying, stimulates satiety
• Administration: subcutaneous injection (daily or weekly), semaglutide also available oral
• Side effects: GI (nausea, vomiting, diarrhea), pancreatitis (<1% risk)
• Contraindications: Pancreatitis
• Does not induce hypoglycaemia
• Efficacy: lowers A1c 0.5-1.4%, weight loss
• There is a reduction in ASCVD outcomes and CV mortality in patients with T2D & CVD taking GLP-1 RA (liraglutide, semaglutide, dulaglutide)

GIP/GLP-1 Receptor Agonist

• Name: Tirzepatide
• Mechanism: synthetic dual-acting agonist, targeting GIP & GLP-1 receptors
• Action: GIP enhances effects of GLP-1, potent glucose-dependent insulin secretion, inhibits glucagon secretion, indirectly slows gastric emptying, stimulates satiety
• Administration: subcutaneous injection weekly
• Side effects: GI (nausea, vomiting, diarrhea), pancreatitis (<1% risk)
• Contraindications: Pancreatitis
• Does not induce hypoglycaemia
• Efficacy: Lowers A1c 2%, weight Loss

DPP IV Inhibitors

• Names: Sitagliptin, linagliptin, vildagliptin, saxagliptin
• Action: increases duration of action of GLP-1 and GIP
• The mechanism inhibits dipeptidyl peptidase-4 with 80% inhibition at 24 hours

DPP IV Inhibitors Metabolism

• Sitagliptin and saxagliptin are not metabolized; excreted unchanged through the kidneys, dose adjusted for renal insufficiency
• Linagliptin is hepatically metabolised
• They are administered once daily by mouth
• Contraindications: pancreatitis
• Adverse effects: gastrointestinal
• Do not induce hypoglycemia and are weight neutral
• Efficacy: lowers A1c ~0.7%

Normal Renal Glucose Handling

• The kidneys filter and reabsorb 180 g of glucose per day
• SGLTs are responsible for this reabsorption
• Majority of glucose (90%) is reabsorbed by SGLT2
• Remaining glucose is reabsorbed by SGLT1 (10%)
• Results in minimal to no glucose excretion

SGLT2 Inhibitors

• Lower blood glucose levels by acting on the kidney by increased urinary excretion of excess glucose (~70 g/day, corresponding to 280 kcal/day*)
• Name: Empagliflozin, canagliflozin, dapagliflozin
• Mechanism: Excretion of 50-100 grams glucose/day
• Metabolism: Mainly hepatic with some metabolites excreted via kidney
• Contraindications: Severe renal impairment, ESRD, or on dialysis
• Side effects: Vulvovaginal candidiasis, vulvovaginal mycotic infection, urinary tract infections, and polyuria, small risk of euglycemic DKA
• Efficacy: lowers A1c by as much as 0.7% (canagliflozin 0.9-1%)
• Weight loss of ~ 2.2%
• • Cardiovascular risk benefit. Also approved for heart failure and CKD

Summary of Diabetes Drugs Effects

• Biguanide (metformin): Decreases weight, used with caution GFR <30
• Sulfonylureas (glipizide): Increases weight, with caution reduced renal clearance in kidney failure
• Alpha-glucosidase inhibitors (acarbose): is weight neutral, with caution in kidney disease
• Thiazolideniones (pioglitazone): Increases Weight, use caution CV events/mortality (rosiglitazone)
• DPP IV inhibitor (sitagliptin): is weight neutral, with caution to pancreatitis
• GLP-1 agonist (semaglutide): Decreases Weight, use caution to Pancreatitis, HF (saxagliptin)
• SGLT-2 inhibitor (dapagliflozin): Decreases Weight, use caution with PAD

This quiz covers the diagnosis, pathophysiology, and treatment approaches for diabetes mellitus, focusing on differentiating between type 1 and type 2 diabetes. It explores insulin resistance, clinical presentations, and the efficacy of antidiabetic drugs in managing glycemic control. The content addresses key aspects of diabetes management and underlying mechanisms.