Diabetes Past Paper PDF

MODULE 4 9 STARVE/FEED CYCLE 10 DIABETES 1 10 DIABETES 2  10. DIABETES – CONTENTS – I. DIABETES TYPE 1 AND DIABETES TYPE 2 II. GLYCEMIA VALUES III. PATHOPHYSIOLOGY OF DIABETES Type 2 Diabetes Hype...

MODULE 4 9 STARVE/FEED CYCLE 10 DIABETES 1 10 DIABETES 2  10. DIABETES – CONTENTS – I. DIABETES TYPE 1 AND DIABETES TYPE 2 II. GLYCEMIA VALUES III. PATHOPHYSIOLOGY OF DIABETES Type 2 Diabetes Hyperglycemia Hypertriacylglycerolemia Type 1 Diabetes Hyperglycemia Hypertriacylglycerolemia Ketoacidosis IV. TREATMENT OF DIABETES TYPE 1 Rapid- and short-acting insulin Intermediate-acting insulin Long-acting insulin V. TREATMENT OF DIABETES TYPE 2 Incretin mimetics Sulfonylureas Biguanides Thiazolidinediones DPP-4 inhibitors SGLT2 inhibitors 3  10. DIABETES – LEARNING OBJECTIVES – Compare diabetes type 1 and diabetes type 2 (age of onset, nutritional status, prevalence). Define the mechanisms for hyperglycemia and hypertriacylglycerolemia in diabetes type 2 Discuss the mechanism of ketoacidosis in diabetes type 1 Distinguish between the different types of insulin preparations and their recommendations for treatment of Type 1 diabetes Discuss the mechanism of insulin secretagogues (sulfonylureas) and compare to insulin secretion from pancreatic b-cells Compare and discuss the mechanism of insulin sensitizers (thiazo- lidinediones and biguanides) 4 DIABETES TYPE 1 AND DIABETES TYPE 2 5 TYPE 1 DIABETES most commonly afflicts children, adolescents, or young adults (but some latent forms occur late in life). Type 1 Diabetes is characterized by a deficiency in insulin due to the impairment of the b cells. Loss of b-cell function fails to respond to glucose. Treatment of Type 1 diabetes requires exogenous insulin. TYPE 2 DIABETES accounts for more than 90% of the cases of diabetes. Type 2 diabetes is influenced by genetic factors, aging, obesity, and –importantly– peripheral insulin resistance. Impairment of metabolism is usually milder than in Type 1 Diabetes. 6  I. DIABETES TYPE I AND DIABETES TYPE II Exogenous insulin is administered to replace absent insulin secretion in type 1 diabetes or to supplement insufficient insulin secretion in type 2 diabetes (T2D). ______________________________________________________________________ Type I Type II _________________________________________________________________________________________________ Age of onset Usually during Commonly over childhood or age 35 puberty _________________________________________________________________________________________________ Nutritional status Commonly Obesity usually at time of onset undernourished present _________________________________________________________________________________________________ Prevalence 5-10% of 90-95% of diagnosed diagnosed diabetics diabetics ________________________________________________________________________________________________ Genetic Moderate Very strong predisposition ________________________________________________________________________________________________ Defect or β cells are destroyed Inability of β cells deficiency eliminating the to produce insulin; production of insulin resistance insulin _________________________________________________________________________________________________ 7  DIABETES In a normal post-absorptive period, constant b-cell secretion maintains low basal levels of circulating insulin. This suppresses lipolysis and glycogenolysis. A burst of insulin secretion occurs after ingesting a meal, in response to transient increases in circulating glucose. This last for up to 15 min, followed by the postprandial secretion of insulin. normal subjects Type 1 Diabetes is characterized by the lack of Insulin [Plasma concentration] (µU/ml) 80 functional b cells and can neither maintain basal secretion of insulin nor respond to variations in Type 2 Diabetics circulating glucose. 40 Type 2 Diabetes is characterized by the lack of sensitivity of target organs to insulin. The pancreas Type 1 Diabetics retains some b cell function, but insulin secretion is 0 0 5 10 insufficient to maintain glucose homeostasis. At Time (min) infusion of glucose variance with Type 1 Diabetes, those with Type 2 diabetes are often obese; obesity contributes to insulin resistance. 8 GLYCEMIA VALUES 9  GLYCEMIA VALUES Fasting State Post-Prandial Glucose Glucose Glucose (minimum) (mg/dl) (maximum) (mg/dl) 2-3 hours after (eating (mg/dl) Hypoglycemia – < 59 < 60 Early hypoglycemia 60 79 60 – 70 Normal 80 100 < 140 Early diabetes 101 126 140 – 200 Diabetes > 126 – > 200 10  I. HbA1c Hemoglobin A1c (HbA1c or A1C) is used to diagnose type 1 and type 2 diabetes, to identify pre-diabetes, and to monitor management of diabetes. Non-enzymic glycation of HbA1c is facilitated by hyper- glycemia and it offers accurate values of glycemia. The higher HbA1c levels, the poorer the glycemia control. Normal HbA1c range: 4.4-5.6%. HOW TO COMPARE Blood Sugar HbA1c 4% 60 (mg/dL) 5% 90 6% 120 7% 150 Normal Prediabetes Diabetes 8% 180 < or = to 5.6 5.7-6.4 6.5+ 180 210 120 150 Blood Glucose 240 270 9% 210 (mg/dL) 90 300 10% 240 11% 270 12% 300 13% 330 11 PATHOPHYSIOLOGY OF DIABETES 12  TYPE 2 DIABETES Type 2 Diabetes (T2D) (noninsulin-dependent diabetes mellitus (NIDDM)) Insulin is present diabetes type II (T2D), albeit at lower levels; the problem, however, is insulin resistance along with insufficient production by b-cells to overcome this resistance. T2D is characterized by: Hyperglycemia occurs mainly because of the poor uptake of glucose by peripheral tissues, particularly muscle and adipose tissue. The expression of the insulin-sensitive GLUT4 in β-cells these tissues is decreased. GLUT2 in liver is not insulin-sensitive and is never saturated. b-cells fats ingested in the diet ¯ insulin GLUT2 insulin 8 fatty acids are oxidized glucose as fuel or esterifiedglucose for storage portal glycogen gallbladder amino amino acids acids adipocyte fat CM fat glucose = lymph HYPERGLYCEMIA small gut intestine GLUT4 7 fatty acids enter cells GLUT4 chylomicrons VLDL 1 bile salts emulsify glucose = dietary fats in the HYPERTRIACYL- lipoprotein lipase triglycerides 6 lipoprotein lipase, activated = small intestine, forming GLYCEROLEMIA by ApoC-II in the capillary mixed micelles converts triacylglycerols to = capillary 2 intestinal lipases intestinal fatty acids and glycerol 5 chylomicrons move = degrade triacylglycerols mucosa 13 through the lymphatic system to tissues  TYPE 2 DIABETES Hypertriacylglycerolemia results from an increase in VLDL without involvement or accumulation of chylomicrons. Hypertriacylglycerolemia is explained by the rapid rates of the de novo synthesis of fatty acids and VLDL rather than increased delivery of fatty β-cellsacids from adipocytes. b-cells fats ingested in the diet ¯ insulin GLUT2 insulin 8 fatty acids are oxidized glucose as fuel or esterifiedglucose for storage portal glycogen gallbladder amino amino acids acids adipocyte fat CM fat glucose = lymph HYPERGLYCEMIA small gut intestine GLUT4 7 fatty acids enter cells GLUT4 chylomicrons VLDL 1 bile salts emulsify glucose = = lipoprotein lipase triglycerides dietary fats in the HYPERTRIACYL- 6 lipoprotein lipase, activated small intestine, forming GLYCEROLEMIA by ApoC-II in the capillary mixed micelles converts triacylglycerols to = capillary 2 intestinal lipases intestinal fatty acids and glycerol 5 chylomicrons move = degrade triacylglycerols mucosa through the lymphatic system to tissues 14 chylomicron  TYPE 1 DIABETES Type I Diabetes (T1D) (insulin-dependent diabetes mellitus (IDDM) In contrast to diabetes type II (T2D), in type I there is a complete absence of insulin production by the pancreas. Hence, blood levels of insulin cannot increase in response to elevated blood levels of glucose. Under these circumstances, the liver remains gluconeogenic and ketogenic, without the ability to switch to glycolysis, glycogenesis, and lipogenesis and, consequentially, without the ability to buffer blood glucose levels. fats ingested a-cells in the diet ¯ glucagon 8 fatty acids are oxidized glucose as fuel or esterifiedglucose for storage amino gluconeogenesis glycogen gallbladder amino acids acids adipocyte lactate fat CM fat HYPERGLYCEMIA ketone glucose = small bodies gut KETOACIDOSIS intestine 7 fatty acids enter cells fatty GLUT4 acids GLUT4 chylomicrons VLDL | glucose 1 bile salts emulsify = dietary fats in the TRIACYLGLY- lipoprotein lipase triglycerides 6 lipoprotein lipase, activated = small intestine, forming CEROLEMIA by ApoC-II in the capillary mixed micelles converts triacylglycerols to = capillary 2 intestinal lipases intestinal fatty acids and glycerol 5 chylomicrons move = degrade triacylglycerols mucosa through the lymphatic 15 system to tissues  TYPE 1 DIABETES Type 1 Diabetes (T1D) (insulin-dependent diabetes mellitus (IDDM)) In contrast to diabetes type II (T2D), in type I there is a complete absence of insulin production by the pancreas. Hence, blood levels of insulin cannot increase in response to elevated blood levels of glucose. Diabetes type I is characterized by: Hyperglycemia. Occurs because hepatic gluconeogenesis is continuous; hence, the liver contributes to hyperglycemia in a well-fed state. Also muscle and adipose tissue fail to incorporate glucose in the absence of insulin because GLUT-4 remains sequestered within the cells, thus contributing further to the hyperglycemia. fats ingested a-cells in the diet ¯ glucagon 8 fatty acids are oxidized glucose as fuel or esterifiedglucose for storage amino gluconeogenesis glycogen gallbladder amino acids acids adipocyte lactate fat fat HYPERGLYCEMIA CM KETOACIDOSIS ketone glucose = small bodies gut GLUT4 intestine 7 fatty acids enter cells fatty GLUT4 chylomicrons VLDL acids | glucose 1 bile salts emulsify TRIACYLGLY- = dietary fats in the CEROLEMIA lipoprotein lipase triglycerides 6 lipoprotein lipase, activated = small intestine, forming by ApoC-II in the capillary mixed micelles converts triacylglycerols to = capillary 2 intestinal lipases intestinal fatty acids and glycerol = degrade triacylglycerols mucosa 5 chylomicrons move 16 through the lymphatic system to tissues  TYPE 1 DIABETES Type 1 Diabetes (insulin-dependent diabetes mellitus (IDDM)) In contrast to diabetes type II (T2D), in type I there is a complete absence of insulin production by the pancreas. Hence, blood levels of insulin cannot increase in response to elevated blood levels of glucose. Diabetes type I is characterized by: Hypertriacylglycerolemia results because VLDL is synthesized and released by the liver more rapidly than these particles can be cleared from the blood by lipoprotein lipase, whose expression is dependent on insulin. fats ingested a-cells in the diet ¯ glucagon 8 fatty acids are oxidized glucose as fuel or esterifiedglucose for storage amino gluconeogenesis glycogen gallbladder amino acids acids adipocyte lactate HYPERGLYCEMIA fat CM fat KETOACIDOSIS ketone glucose = small bodies gut GLUT4 intestine 7 fatty acids enter cells fatty GLUT4 chylomicrons VLDL acids | 1 bile salts emulsify TRIACYLGLY- glucose = dietary fats in the CEROLEMIA lipoprotein lipase triglycerides 6 lipoprotein lipase, activated = small intestine, forming by ApoC-II in the capillary mixed micelles converts triacylglycerols to = capillary 2 intestinal lipases intestinal fatty acids and glycerol 5 chylomicrons move = degrade triacylglycerols mucosa 17 through the lymphatic system to tissues  TYPE 1 DIABETES Type 1 Diabetes (insulin-dependent diabetes mellitus (IDDM)) In contrast to diabetes type II (T2D), in type I there is a complete absence of insulin production by the pancreas. Hence, blood levels of insulin cannot increase in response to elevated blood levels of glucose. Diabetes type I is characterized by: Ketoacidosis develops because the rate of lipolysis in adipose tissue is uncontrolled (presence of glucagon and absence of insulin), thus resulting in increased plasma levels of fatty acids and their further transformation into ketone bodies in the liver. The excess of fatty acids that liver cannot metabolize to ketone bodies is esterified and directed into VLDL synthesis. fats ingested a-cells in the diet ¯ glucagon 8 fatty acids are oxidized glucose as fuel or esterifiedglucose for storage amino gluconeogenesis glycogen gallbladder amino acids acids adipocyte lactate HYPERGLYCEMIA fat CM fat KETOACIDOSIS ketone glucose = small bodies gut GLUT4 intestine 7 fatty acids enter cells fatty GLUT4 chylomicrons VLDL acids TRIACYLGLY- | 1 bile salts emulsify CEROLEMIA lipoprotein lipase triglycerides glucose = = dietary fats in the 6 lipoprotein lipase, activated small intestine, forming by ApoC-II in the capillary mixed micelles converts triacylglycerols to = capillary 2 intestinal lipases intestinal fatty acids and glycerol 5 chylomicrons move = 18 degrade triacylglycerols mucosa through the lymphatic system to tissues  TYPE I DIABETES Type 1 Diabetes (insulin-dependent diabetes mellitus (IDDM)) The overall picture is that every tissue in type I diabetes plays a catabolic role as in starvation, despite the delivery of adequate fuel from the gut. Diabetes type I is characterized by: Hyperglycemia occurs because hepatic gluconeogenesis is continuous; hence, the liver contributes to hyperglycemia in ­Hepatic gluconeogenesis a well-fed state. Muscle and adipose tissue fail to incorporate ¯Glucose uptake glucose in the absence of insulin because GLUT-4 remains sequestered within the cells, thus contributing further to the hyperglycemia. Hypertriacylglycerolemia results because VLDL is ­Liver VLDL synthesis synthesized and released by the liver more rapidly than ¯Lipoprotein lipase activity these particles can be cleared from the blood by lipoprotein lipase, whose expression is dependent on insulin. 19  TYPE 1 DIABETES Type 1 Diabetes (insulin-dependent diabetes mellitus (IDDM)) The overall picture is that every tissue in type I diabetes plays a catabolic role as in starvation, despite the delivery of adequate fuel from the gut. Diabetes type I is characterized by: Ketoacidosis develops because the rate of lipolysis in adipose tissue is uncontrolled (presence of glucagon and absence of insulin), thus resulting in increased ­Lipolysis in adipose tissue plasma levels of fatty acids and their further ­Liver fatty acid oxidation transformation into ketone bodies in the liver. The ­Ketogenesis in liver excess of fatty acids that liver cannot metabolize to ketone bodies is esterified and directed into VLDL synthesis. 20  TREATMENT OF TYPE 1 DIABETES 21  III. DRUGS FOR OBESITY TREATMENT The TYPS website: http://typs.acadoinformatics.com/ includes several educational modules linked to various courses; you can practice basic drug information with practice questions on brand/generic, therapeutic category, indication and dosing of drugs. The content is based on the Top 300 drug list. 22 TYPE 1 DIABETES most commonly afflicts children, adolescents, or young adults (but some latent forms occur late in life). Type 1 Diabetes is characterized by a deficiency in insulin due to the impairment of the b cells. Loss of b-cell function fails to respond to glucose. Treatment of Type 1 diabetes requires exogenous insulin. 23  II. INSULIN Insulin is a polypeptide consisting of two chains, a and b, linked by 2 interchain disulfide bridges. α chain | | S S | | S S β chain | | Insulin is synthesized by the b cells of pancreas as pro-insulin. In Golgi, pro-insulin is converted to insulin and secreted by secretory granules together with C peptide. a chain C peptide b chain PROINSULIN Proteolitic cleavage (trypsin-like enzymes) INSULIN | | S S | | S S | | + 24  INSULIN Treatment of Type 1 diabetes requires Insulin is a polypeptide consisting of two chains, a and b, linked by 2 interchain disulfide bridges. exogenous insulin. Insulin and C peptide α chain | S | | S | are secreted by the b cells of pancreas. S S β chain | | Insulin undergoes significance liver and Insulin is synthesized by the b cells of pancreas as pro-insulin. In Golgi, pro-insulin is converted to insulin and secreted by secretory granules kidney extraction; hence, plasma levels of together with C peptide. insulin may not reflect accurately insulin a chain C peptide b chain PROINSULIN production. Therefore, measurement of C Proteolitic cleavage (trypsin-like enzymes) peptide may be a better index of insulin INSULIN | | levels. S S | S | | S | Exogenous insulin is administered to + replace absent insulin secretion in Type 1 diabetes. 25 Human exogenous insulin is produced by recombinant DNA using strains of E coli or yeast genetically altered to contain the gene of human insulin. Because insulin is a polypeptide, it is degraded in the gastrointestinal tract if taken orally. Exogenous insulin is administered by sub- cutaneous injection. Insulin pumps (continuous subcutaneous insulin infusion) is another method of insulin delivery that may be more convenient for some patients. Modification of amino acid sequence of human insulin results in different preparations with faster onset and shorter duration of action than regular insulin: Regular Insulin Insulin lispro Insulin aspart Insulin glulisine Adverse reactions to insulin: Hypoglycemia is the most serious and common adverse reaction to insulin. Other adverse reactions include weight gain and lipodystrophy (that can be minimized by rotation of injection sites). 26  INSULIN PREPARATIONS AND TREATMENT Insulin preparations are classified as rapid- and short-, intermediate-, or long-acting: Rapid- and short-acting insulin preparations – Regular insulin, insulin lispro, insulin aspart, and insulin glulisine are examples. Regular insulin is a short-acting preparation, whereas insulin lispro, insulin aspart, and insulin glulisine are rapid-acting insulins. These insulins are administered to mimic the prandial (mealtime) release of insulin and to control postprandial glucose. insulin lispro insulin aspart insulin glulisine regular insulin [Insulin] plasma 0 6 12 18 24 Time (hours) 27  INSULIN PREPARATIONS AND TREATMENT Insulin preparations are classified as rapid- and short-, intermediate-, or long-acting: Intermediate-acting insulin preparations – Neutral protamine Hagedorn (NPH) is an intermediate-acting insulin following the addition of Zn and protamine to regular insulin. The combination with protamine results in delayed absorption and longer duration of action. It is used for basal (fasting) control of type 1 diabetes. NPH should be given only subcutaneously. NPH insulin [Insulin] plasma 0 6 12 18 24 Time (hours) 28  INSULIN PREPARATIONS AND TREATMENT Insulin preparations are classified as rapid- and short-, intermediate-, or long-acting: Long-acting insulin preparations – The isoelectric point of insulin glargine is lower than that of human insulin, leading to formation of a precipitate that releases insulin over an extended period resulting in a prolonged hypoglycemic effect. It is used for basal control and should only be administered subcutaneously. Insulin detemir has a fatty acid side chain and results in slow dissociation from albumin. Insulin detemir [Insulin] plasma Insulin glargine 0 6 12 18 24 Time (hours) 29  INSULIN PREPARATIONS AND TREATMENT Insulin preparations are classified as rapid- and short-, intermediate-, or long-acting: Rapid- and short-acting insulin preparations –These insulins are administered to mimic the prandial (mealtime) release of insulin and to control postprandial glucose. Intermediate-acting insulin preparations – Are used for basal (fasting) control of type 1 diabetes. NPH should be given only subcutaneously. Long-acting insulin preparations – It is used for basal control and should only be administered subcutaneously. insulin lispro insulin aspart insulin glulisine regular insulin NPH insulin detemir insulin [Insulin] plasma glargine 0 6 12 18 24 Time (hours) 30 31 32 33  TREATMENT OF TYPE 2 DIABETES 35 — MAJOR FACTORS CONTRIBUTING TO HYPERGLYCEMIA —  INSULIN RESISTANCE IN PERIPHERAL TISSUES LIVER LIVER ↑ Increased gluconeogenesis ↑ Increased gluconeogenesis GLUCOSE ↓ Decreased glucose uptake GLUCOSE ↓↓Decreased GLUT4 glucose uptake ↓ GLUT4 ADIPOSE MUSCLE TISSUE ADIPOSE MUSCLE TISSUE  INADEQUATE INSULIN SECRETION FROM b CELLS PANCREAS INSULIN PANCREAS INSULIN 36 — MAJOR FACTORS CONTRIBUTING TO HYPERGLYCEMIA — Normal glucose tolerance Insulin resistance Age Impaired glucose tolerance Obesity Increasing hyperglycemia VICIOUS CYCLE Impaired metabolism-secretion Insulin secretion Coupling reduced DIABETES 37  III. PHARMACOLOGY OF DIABETES TYPE II — INCRETIN MIMETICS — Incretin hormones are released from the gut in response to a meal (e.g., after glucose ingestion); incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic polypeptide (GDIP). Incretin hormones are responsible for about 70% of postprandial insulin secretion. Examples of incretin mimetics (injectable) are liraglutide and semaglutide that are analogs of GLP-1 and exert their activity by acting as GLP-1 receptor agonist. Liraglutide and semaglutide improve glucose- dependent insulin secretion and promote b-cell proliferation. Treatment with liraglutide and semaglutide is usually associated with weigh loss because it enhances satiety. All other oral agents are associated with weigh gain. GUT incretin hormones SEMAGLUTIDE LIRAGLUTIDE GDIP glucose GLP-1 GLP1 receptor insulin secretion (postprandial) 38  III. PHARMACOLOGY OF DIABETES TYPE II — INCRETIN MIMETICS — Type II Diabetes (T2DM) has been identified as a risk factor for Alzheimer’s disease. Furthermore, insulin signaling is impaired in Alzheimer’s disease patients, thus contributing to its pathological features. Hence, normalizing insulin signaling in the brain is a viable strategy for Alzheimer’s disease treatment. In a range of mouse models of Alzheimer’s disease, GLP-1 receptor agonists (liraglutide) were found to be neuroprotective. GUT incretin hormones SEMAGLUTIDE LIRAGLUTIDE GDIP glucose GLP-1 GLP1 receptor insulin secretion (postprandial) Hölscher, C. (2020) Expert Opinion on Investigational Drugs 20, 333-348 39  REGULATION OF INSULIN SECRETION BY THE b CELLS OF PANCREAS Insulin secretion is regulated by blood glucose glucose levels; glucose is taken up by the glucose glucokinase glucose transporter in the b cells, phospho- glu-6P rylated by glucokinase (glucose sensor). Metabolism of glucose (glycolysis, oxida- pyruvate ATP tive phosphorylation) generates ATP; rise in ATP blocks the K+ channels, leads to block K+ channel membrane depolarization and Ca2+ influx. membrane depolarization The increase in intracellular Ca2+ causes Ca2+ Ca2+ insulin exocytosis upon microfilament insulin contraction. secretory granules Golgi 40  PHARMACOLOGY OF TYPE II DIABETES — SULFONYLUREAS — Sulfonylureas are classified as insulin glyburide secretagogues: they promote insulin release from the b cells of pancreas. Sulfonylureas block the ATP-sensitive K+ channels, result- block K+ channel SULFONYLUREAS membrane ing in Ca2+ influx, and insulin exocytosis depolarization upon microfilament contraction. Ca2+ Ca2+ Examples of sulfonylureas are glyburide, insulin glipizide, and glimepiride. secretory granules 41 Insulin Icodec is a long-lasting basal insulin analogue with a half-life of 196 INSULIN ICODEC hours (8 days). Once injected, insulin Insulin icodec Insulin icodec binds strongly but reversibly to IGF1 IR albumin (similar behavior as insulin detemir but not to the same extent), thus resulting in a continuous, slow and steady IRS Ras GDP reduction of blood sugar over the week. Grb2 PI3K The injection volume of once-weekly PIP2 Ras GTP insulin icodec is equivalent to daily insulin PTEN PIP3 glargine U100. Insulin Icodec binds to the insulin receptor Akt Erk to activate the same signaling pathways to give the same full metabolic effects as human insulin. cell growth survival survival cell growth Approved for Type 2 Diabetes, FDA differentiation neuroplasticity signals differentiation approval is expected in 2024.  III. PHARMACOLOGY OF DIABETES TYPE II — BIGUANIDES — Metformin is a biguanide and is considered as an insulin sensitizer. Mechanism of action: Metformin has poor plasma membrane permeability but uptake into many cells (including hepatocytes) is promoted by the organic cation transporter OCT1. Metformin is the most appropriate initial oral agent for the management of type 2 diabetes metformin in patients with no comorbidities. Long-term use of metformin may be associated with vitamin B12 deficiency. Periodic measurements of B12 levels are recommended, especially in patients with anemia or peripheral neuropathy. 43  III. PHARMACOLOGY OF DIABETES TYPE II — BIGUANIDES — Metformin: inhibits complex I of the mitochondrial respiratory chain, thus leading to inhibition of ATP synthesis, thereby increasing AMP/ATP ratios, a condition for activation of AMPK activates AMPK but not directly (as a consequence of increased AMP) METFORMIN GLUCAGON glucose —OCT GLUT2 \ AC ↓cAMP ↓PKA metformin ATP ↑AMPK ↑F-2,6-P ADP ADP↑ AMP↑ ATP ATP↓ PFPase gluconeogenesis pyruvate F-1,6-bisP F-6-P G-6-P PFK 44  III. PHARMACOLOGY OF DIABETES TYPE II — BIGUANIDES — Metformin: inhibits phosphofructophosphatase reduces hepatic glucose production (gluconeogenesis) enhances peripheral insulin sensitivity METFORMIN GLUCAGON glucose —OCT GLUT2 \ AC ↓cAMP ↓PKA metformin ATP ↑AMPK ↑F-2,6-P ADP ADP↑ AMP↑ ATP ATP↓ PFPase gluconeogenesis pyruvate F-1,6-bisP F-6-P G-6-P PFK 45  III. PHARMACOLOGY OF DIABETES TYPE II — THIAZOLIDINEDIONES — Thiazolidinediones (TZDs) are insulin sensitizers. Examples are pioglitazone and rosiglitazone. Mechanism of action: thiazolidinediones lower S insulin resistance by acting as agonists for a R O nuclear hormone receptor, the peroxisome N O proliferator activated receptor-g (PPARg). This thiazolidineone functional group occurs mostly on adipose tissue but the effects of TZDs extend to skeletal muscle and liver. Bind- ing of TZDs to PPARg results in transcription of genes that increase glucose uptake and utilization as well as several genes related to lipid metabolism: the end result is increase uptake of fatty acids from plasma by adipocytes. Glucose Uptake (GLUT4) Glucose Utilization TZD Genes Lipoprotein lipase PPARγ fatty acid transporter fatty acyl-CoA synthase Adipocyte differentiation 46  III. PHARMACOLOGY OF DIABETES TYPE II — THIAZOLIDINEDIONES — Thiazolidinediones (TZDs) are insulin sensitizers. Examples are pioglitazone and rosiglitazone. Mechanism of action: thiazolidinediones lower S insulin resistance by acting as agonists for a R O nuclear hormone receptor, the peroxisome N O proliferator activated receptor-g (PPARg). This thiazolidineone occurs mostly on adipose tissue but the effects functional group of TZDs extent to skeletal muscle and liver. Importantly, TZDs block the inhibitory action of TNFα (produced by adipocytes) on insulin signaling. Pioglitazone decreases triglyceride levels and increase HDL cholesterol. Rosiglitazone is less used due to cardiac adverse effects (increases LDL cholesterol and triglycerides). Glucose Uptake (GLUT4) Glucose Utilization TZD Genes Lipoprotein lipase PPARγ fatty acid transporter fatty acyl-CoA synthase Adipocyte differentiation 47  III. PHARMACOLOGY OF DIABETES TYPE II — THIAZOLIDINEDIONES — glucose Thiazolidinediones (TZDs) are insulin sensitizers. Mechanism of action: In addition to the effect pyruvate lactate of TZDs on PPARg, some newly synthesized TZD TZDs inhibit the mitochondrial pyruvate carrier CYTOSOL (MPC) by a PPARg-independent mechanism; inhibition of MPC leads to attenuation of INNER GLUCONEOGENESIS MITOCHONDRIAL MEMBRANE hyperglycemia and increased insulin sensitivity. pyruvate MPC is also known as mTOT (mitochondrial PC PDH Target of Thiazolidinedione) acetyl-CoA S oxaloacetate citrate R O N O N thiazolidineone malate isocitrate functional group O TCA O fumarate α-KG S O MSDC-0160 N glutamine O succinate succinyl-CoA  III. PHARMACOLOGY OF DIABETES TYPE II — DIPEPTIDYL PEPTIDASE-4 INHIBITORS — Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as linagliptin and sitagliptin, inhibit DPP-4, thus prolonging the effect of incretin hormones. Incretin hormones, released from the gut, are responsible for about 70% of postprandial insulin secretion. Example of an incretin mimetic (injectable) is liraglutide. The latter improves glucose-dependent insulin secretion, and promote b-cell proliferation. LIRAGLUTIDE GUT inactive incretin incretin hormones hormones glucose GLP-1 GLP-1inactive GDIP DPP-4 GDIPinactive insulin LINAGLIPTIN secretion (postprandial) 49  III. PHARMACOLOGY OF DIABETES TYPE II — SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITORS — Sodium-glucose co-transporter 2 (SGLT2) is responsible for reabsorbing filtered CANAGLIFLOZIN glucose in the kidney; inhibitors of SGLT2 (canagliflozin) decrease glucose reabsorp- Na+ Na+ Glucose Glucose tion, increase glucose urinary excretion, and lower blood glucose. Simultaneously, these SGLT2 inhibitors of SGLT2 decrease Na+ reabsorp- tion. 50  III. PHARMACOLOGY OF DIABETES TYPE II — MAJOR SITES OF ACTION OF HYPOGLYCEMIC DRUGS — SULFONYLUREAS THIAZOLIDINEDIONES SGLT2 INHIBITORS HYPERGLYCEMIA Duration of action of some oral hypoglycemic agents glyburide 18 hours METFORMIN glipizide 20 hours THIAZOLIDINEDIONES THIAZOLIDINEDIONES metformin 6 hours pioglitazone >24 hours 51  III. PHARMACOLOGY OF DIABETES TYPE II — SUMMARY— MECHANISM OF ACTION PLASMA INSULIN SULFONYLUREAS Glyburide Stimulate insulin secretion Glipizide BIGUANIDES Metformin Decreases liver gluconeogenesis THIAZOLIDINEDIONES Pioglitazone Binds to PPARg; decreases insulin resistance DPP-4 INHIBITORS Linagliptin Increase glucose-dependent insulin Sitagliptin release INCRETIN MIMETICS Liraglutide Increases glucose-dependent insulin release; decreases glucagon secretion SGLT2 INHIBITORS Canagliflozin Increases kidney glucose excretion 52