Diabetes Mellitus: Types and Complications

• Diabetes Mellitus (DM) refers to a group of chronic metabolic disorders distinguished by persistent hyperglycemia due to defects in insulin secretion, insulin action, or both.

Types of Diabetes Mellitus

• Type 1 DM (T1DM) involves the autoimmune destruction of pancreatic β-cells, resulting in absolute insulin deficiency, and generally has an abrupt onset, occurring in younger individuals.
• Type 2 DM (T2DM) is characterized by insulin resistance and a relative insulin deficiency, which develops gradually and is often linked to obesity and metabolic syndrome.
• Gestational DM is glucose intolerance initially identified during pregnancy, which usually resolves postpartum but elevates the future risk for T2DM.

Macrovascular Complications of DM

• Include coronary artery disease (myocardial infarction), cerebrovascular disease (stroke), and peripheral arterial disease.

Microvascular Complications of DM

• Include diabetic retinopathy (eye disease), nephropathy (kidney disease), and neuropathy (nerve damage).

Benefits of Glucose Control on Complications

• In T1DM, strict glycemic control lessens both microvascular complications (retinopathy, nephropathy, neuropathy) and macrovascular risk, particularly over the long term.
• In T2DM, improved glycemic control reduces microvascular complications, but the evidence for macrovascular benefit varies based on how control is achieved because weight gain and adverse metabolic effects from some therapies might negate benefits.

Prevalence of T1DM versus T2DM

• T2DM accounts for roughly 90% of all diabetes cases, while T1DM makes up about 5–10% of cases.

Populations at Highest Risk for T2DM

• Increased risk is seen in African Americans, Latinos, Native Americans, Asian Americans, and Pacific Islanders.
• Also, individuals who are overweight or obese, physically inactive, or with a family history of diabetes are at increased risk.

Opposing Regulatory Effects of Insulin and Glucagon

• Insulin lowers blood glucose by promoting cellular uptake (via GLUT-4 translocation), stimulating glycogenesis, lipogenesis, and inhibiting gluconeogenesis and glycogenolysis.
• Glucagon elevates blood glucose by stimulating glycogenolysis and gluconeogenesis in the liver and by promoting lipolysis.

Exocrine and Endocrine Functions of the Pancreas

• Exocrine function involves secreting digestive enzymes (amylase, lipase, and proteases) and bicarbonate through acinar cells via the pancreatic duct to the duodenum.
• Endocrine function involves secreting hormones (insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin) from the islets of Langerhans.

Functions of Key Pancreatic Structures

• Acini are clusters of exocrine cells that produce and secrete digestive enzymes.
• Islets of Langerhans are clusters of endocrine cells (α-cells, β-cells, δ-cells, PP cells, and ε-cells) that produce hormones regulating glucose metabolism.
• The Pancreatic Duct conveys digestive enzymes from the acinar cells into the duodenum.

Differentiation of α- and β-Cells

• α-Cells produce glucagon, which increases blood glucose levels.
• β-Cells produce insulin, which lowers blood glucose levels.

Processes Regulating Insulin Release

• Triggered primarily by rising blood glucose; the key steps include: Glucose uptake via GLUT-2 (in β-cells).
• Metabolism generates Adenosine Triphosphate (ATP), which raises the ATP/Adenosine Diphosphate (ADP) ratio.
• Closure of ATP-sensitive K⁺ channels encourages Membrane depolarization and opening of voltage-gated Ca²⁺ channels.
• Influx of Ca²⁺ results in the exocytosis of insulin granules.
• Additional stimulators include amino acids and incretin hormones (e.g., GLP-1, GIP).

Cellular Processes in Insulin Release

• The steps of glucose entry, ATP production, channel modulation, and Ca²⁺ influx lead to the exocytotic release of pre-stored insulin.

Structure and Processing of Insulin

• Insulin is synthesized as preproinsulin in the rough endoplasmic reticulum and converted to proinsulin in the Golgi apparatus.
• Cleavage of the C-peptide from proinsulin produces mature insulin, which consists of A- and B-chains linked by disulfide bonds.

Effects of Epinephrine on Glucose Metabolism

• Epinephrine stimulates glycogenolysis, gluconeogenesis, and lipolysis, increasing blood glucose during stress ("fight or flight" responses).

Effects of Insulin Binding to Its Receptor

• Binding activates the insulin receptor’s tyrosine kinase activity, starting a cascade that results in the Translocation of GLUT-4 transporters to the cell membrane.
• Binding also leads to Enhanced glucose uptake, Increased glycogen synthesis and storage.
• It further leads to Inhibition of hepatic gluconeogenesis, and Promotion of lipogenesis.

Processes Regulating Glucagon Release

• Glucagon release is stimulated by low blood glucose, high plasma amino acids, and elevated epinephrine.
• It is inhibited by high blood glucose, insulin, and incretin hormones.

Structure and Processing of Glucagon

• Glucagon is produced as preproglucagon in α-cells; post-translational processing (cleavage) yields the active glucagon peptide.

Effects of Glucagon Binding to Its Receptor

• Binding activates a Gs protein–coupled receptor on hepatocytes, increasing intracellular cyclic Adenosine Monophosphate (cAMP)
• This leads to the activation of protein kinase A (PKA) and subsequent stimulation of glycogenolysis and gluconeogenesis.

Biological Role of Amylin

• Co-secreted with insulin (at approximately a 1:100 ratio).
• Amylin slows gastric emptying, suppresses glucagon secretion, and promotes satiety, contributing to postprandial glucose control.

Role of Renal Sodium-Glucose Cotransporters

• Sodium-glucose cotransporter 2 (SGLT2) (accounts for ~90% of reabsorption) and SGLT1 (~10%) are located in the proximal convoluted tubule.
• They are responsible for reabsorbing filtered glucose; their saturation during hyperglycemia can lead to glycosuria.

Biological Role of Glucagon-like peptide 1(GLP-1) and Gastric inhibitory polypeptide (GIP)

• These incretin hormones enhance insulin secretion (in a glucose-dependent manner) and suppress glucagon release.
• GLP-1 additionally slows gastric emptying and promotes satiety.

Digestion, Absorption, and Transport of Glucose

• Dietary carbohydrates are broken down into monosaccharides (primarily glucose) in the gastrointestinal tract, absorbed via intestinal transporters (e.g., SGLT1, GLUT2), and transported via the portal circulation to the liver.

Role of Glucose Metabolism in Cellular Respiration

• Glucose is the primary fuel for ATP production; it undergoes glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation to generate energy.

Definition of Cellular Respiration

• The process of converting biochemical energy from nutrients (glucose, fats, proteins) into ATP, balancing catabolic (energy-releasing) and anabolic (energy-consuming) pathways.

Role of Glucose, Fats, and Protein in Energy Formation

• Glucose provides immediate energy.
• Fats serve as a dense energy storage source.
• Proteins are primarily used for structural and functional roles but can be converted to energy when needed.

Metabolic Pathways Involving Glucose

• Glycolysis, glycogenesis, glycogenolysis, gluconeogenesis, and the pentose phosphate pathway are key routes that either extract energy from or store glucose.

Role of Glucose Phosphorylation

• Phosphorylation of glucose (by hexokinase or glucokinase) traps it within cells and prepares it for metabolic pathways (e.g., glycolysis).

Differences Between Hexokinase and Glucokinase

• Hexokinase has a low Michaelis constant (Km) (high affinity), is found in most tissues, and is inhibited by its product (glucose-6-phosphate (G6P)).
• Glucokinase has a high Km (lower affinity), is present in liver and pancreatic β-cells, and is not inhibited by G6P, playing a key role in postprandial glucose handling and insulin secretion.

Description of Glycolysis

• A ten-step anaerobic process converts one molecule of glucose into two molecules of pyruvate, producing a net gain of 2 ATP and 2 NADH.

Tricarboxylic Acid Cycle and Oxidative Phosphorylation

• The TCA Cycle (Krebs Cycle) oxidizes acetyl CoA to CO₂, thus generating NADH and Flavin adenine dinucleotide (FADH₂).
• Oxidative Phosphorylation uses electrons from NADH/FADH₂ in the electron transport chain to produce ATP via chemiosmosis.

Functions of Key Metabolites

• Glucose-6-Phosphate (G6P) serves as a central intermediate for glycolysis, glycogen synthesis, and the pentose phosphate pathway.
• Pyruvate is the end product of glycolysis that is converted to acetyl CoA in the mitochondria.
• Acetyl CoA enters the TCA cycle for further oxidation.
• NADH/FADH₂ are electron carriers that drive ATP production in the electron transport chain.

Glycogenesis versus Glycogenolysis

• Glycogenesis involves the synthesis of glycogen from glucose for storage.
• Glycogenolysis involves the breakdown of glycogen to release glucose when needed.

Gluconeogenesis and Its Role

• The process of synthesizing glucose from non-carbohydrate substrates (e.g., amino acids, glycerol) in the liver and kidneys is vital during prolonged fasting.

Definition of the Pentose Phosphate Pathway

• A metabolic pathway parallel to glycolysis produces ribose-5-phosphate for nucleotide synthesis and NADPH for reductive biosynthetic reactions.

Allosteric Regulation of Glucose Metabolic Pathways

• Key enzymes (such as phosphofructokinase-1) are regulated by effectors (e.g., ATP, AMP, citrate) to modulate pathway flux based on cellular energy status.

Hormonal Regulation of Glucose Metabolism

• Hormones (insulin and glucagon) regulate enzyme activities via phosphorylation/dephosphorylation, shifting metabolism between energy storage (anabolism) and energy release (catabolism).

Energy Using and Producing Steps

• Energy-using steps include early phosphorylation reactions in glycolysis and certain steps in gluconeogenesis.
• Energy-producing steps include ATP generation via substrate-level phosphorylation in glycolysis/TCA and oxidative phosphorylation.

Metabolic Changes in Absorptive vs. Fasting States

• Absorptive State (Fed): High insulin leads to glycolysis, glycogenesis, and lipogenesis in the liver, enhanced glucose uptake and lipogenesis in adipose tissue and inhibited lipolysis with increased glycogen synthesis and glycolysis in skeletal muscle.
• Fasting State: Low insulin/high glucagon promote glycogenolysis and gluconeogenesis in the liver, activation of lipolysis releasing free fatty acids in adipose tissue, and increased fatty acid oxidation and proteolysis for gluconeogenic substrates in skeletal muscle.

Biological Effects of Insulin vs. Glucagon

• Insulin increases glucose uptake, stimulates glycogenesis, and inhibits glycogenolysis, gluconeogenesis, and lipolysis.
• Glucagon enhances glycogenolysis and stimulates gluconeogenesis promoting lipolysis while inhibiting glycogenesis.

Ketone Body Formation and Biological Role

• Excess acetyl CoA (from fatty acid oxidation during fasting or insulin deficiency) is converted in the liver to ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone).
• Ketone bodies serve as an alternative energy source, especially for the brain during prolonged fasting or in uncontrolled diabetes.

Pathophysiological Differences: T1DM vs. T2DM

• Type 1 Diabetes Mellitus (T1DM) is an autoimmune destruction of β-cells leading to absolute insulin deficiency, typically having an acute onset with a risk of diabetic ketoacidosis (DKA).
• Type 2 Diabetes Mellitus (T2DM) is insulin resistance with relative insulin deficiency, gradual onset, is often associated with obesity, and has a higher risk of hyperosmolar hyperglycemic state (HHS).

Factors Contributing to Insulin Resistance

• Obesity (especially central adiposity), physical inactivity, genetic predisposition, dyslipidemia, and chronic inflammation (cytokine release from adipose tissue).

Acute and Chronic Complications in T1DM vs. T2DM

• Acute: T1DM commonly presents with DKA, while T2DM more often presents with HHS.
• Chronic: Both types develop microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular disease. Glycation of proteins (AGE formation) plays a key role in tissue damage.

Role of Advanced Glycation End-products (AGEs) and Receptor for Advanced Glycation End-products (RAGE)

• AGEs form when proteins and lipids become glycated in the setting of hyperglycemia.
• Binding of AGEs to their receptor (RAGE) activates pro-inflammatory signaling pathways and contributes to vascular and tissue damage.

Classic Symptoms of Undiagnosed Diabetes

• Polyuria, polydipsia, polyphagia, weight loss, blurred vision, fatigue, and poor wound healing.

General Characteristics: T1DM vs. T2DM

• Type 1 Diabetes Mellitus (T1DM) typically affects younger patients, is associated with a lean body habitus, has an abrupt onset, and is prone to DKA.
• Type 2 Diabetes Mellitus (T2DM) is more common in older or overweight individuals, has a gradual onset, and is often associated with insulin resistance and metabolic syndrome.

Using A1c to Determine Diabetes/Risk

• An A1c ≥6.5% is diagnostic for diabetes, while values between 5.7–6.4% suggest prediabetes and increased risk

Definition of A1c/HbA1c

• A1c is the percentage of hemoglobin with glucose bound to it, reflecting the average blood glucose level over the past 3 months.

GLP-1 Receptor Agonists (GLP-1RAs)

• Mimic the incretin hormone GLP-1 by binding to its receptor on pancreatic β-cells.
• This enhances glucose-dependent insulin secretion, suppresses glucagon release, and slows gastric emptying.
• Some are formulated for once-weekly dosing (e.g., dulaglutide, semaglutide injection), while others are dosed daily (e.g., exenatide twice daily, liraglutide daily).
• Administered via subcutaneous injection, though oral semaglutide (Rybelsus) is available as a tablet.
• May delay gastric emptying, altering the absorption of orally administered drugs.
• Primarily act on GLP-1 receptors in pancreatic β-cells and also affect receptors in the gastrointestinal tract and brain.
• Typically degraded by proteolytic enzymes; some agents have been modified (e.g., by albumin binding) to extend their half-life.

Insulin

• Rapid-acting insulins (e.g., lispro, aspart, glulisine) have a quick onset and are used primarily for mealtime (bolus) dosing and in insulin pumps.
• Long-acting insulins (e.g., glargine, detemir, degludec) provide a steady, prolonged basal insulin level.
• Afrezza is the only inhaled insulin available; it’s a rapid-acting formulation designed for mealtime use.
• Only rapid-acting insulins are used in pump therapy because their quick onset and short duration match the needs for precise bolus dosing.
• Effects can be modified by medications that influence blood glucose (e.g., beta-blockers, corticosteroids).
• Binds to insulin receptors in liver, muscle, and adipose tissue to facilitate glucose uptake and inhibit hepatic glucose production.
• Mainly cleared by the liver and kidneys.
• Injectable insulins must be stored in the refrigerator and should not be frozen.

SGLT Inhibitors

• Most available agents primarily inhibit SGLT2 (e.g., canagliflozin, dapagliflozin, empagliflozin).
• Sotagliflozin inhibits both SGLT1 (affecting intestinal glucose absorption) and SGLT2 (affecting renal glucose reabsorption).
• Can interact with diuretics and other drugs affecting renal function.
• Act in the kidney by inhibiting the sodium-glucose co-transporters (SGLT2 in the proximal tubule; SGLT1 in the gut and kidney for dual inhibitors).
• Primarily metabolized through glucuronidation and excreted via urine and bile.

DPP-4 Inhibitors

• Prevent the degradation of endogenous incretin hormones (like GLP-1), modestly increasing their levels.
• Adding a DPP-4 inhibitor to a GLP-1RA does not provide additional benefit because the GLP-1 receptor is already maximally stimulated.
• Generally well-tolerated, but caution is advised in patients with renal impairment since some are renally cleared.
• Inhibit the DPP-4 enzyme, which is widely distributed in the body, prolonging the activity of incretin hormones.
• Often renally excreted, though the metabolic pathway can vary slightly among agents.

Rybelsus Stability

• Oral tablet should be stored separately from other medications to avoid moisture and potential contamination.
• Rybelsus has its own specific temperature and handling requirements (generally room temperature once dispensed, following the manufacturer’s instructions).