Exocrine vs. Endocrine Pancreas Diabetes Mellitus Drug Treatments - PowerPoint PPT Presentation

Exocrine vs. Endocrine Pancreas Diabetes Mellitus Drug Treatments for Type 2 Diabetes Mellitus Patient F

Endocrine vs. exocrine pancreas islet of Langerhans à endocrine secretion to bloodstream duct cells acinar cells and duct cells à exocrine secretion via ducts to the GI tract to the duodenum acinar cells

Pancreas islets of Langerhans (pancreatic islets): pale- staining regions Low magnification view of the pancreas

Pancreas pale cells are endocrine (hormone-secreting) cells in the pancreatic islet: beta cells: secrete insulin • alpha cells: secrete glucagon • each dark cluster is an acinus containing acinar cells (duct cells not visible) High magnification view of the pancreas

Acinar cells secrete inactive enzyme precursors called zymogens electron micrograph showing acinar cells with dark zymogen granules and abundant rough ER Figure 15.15c from Wheater’s Functional Histology

Role of hormones in endocrine pancreas: regulating metabolism in the fed and fasted states after a meal, insulin • promotes nutrient uptake, nutrient utilization, and synthesis of energy stores* *energy stores: glycogen and triacylglycerol • during fasting, glucagon promotes hepatic glucose production Figure 22.14a and b, p. 709

Cellular action of insulin cell membrane à insulin increases glucose uptake from the plasma by increasing glucose transporters in the cell membrane

Insulin is part of the negative feedback loop that regulates plasma glucose levels

Diabetes mellitus Type 1 diabetes mellitus (T1DM) • autoimmune destruction of pancreatic beta cells • ~5% of diabetics • treatment requires insulin injections Type 2 diabetes mellitus (T2DM) insulin resistance with defects in insulin secretion ~95% of diabetics ~80-85% of type 2 diabetics are overweight

Both T1DM and T2DM cause hyperglycemia T1DM: absolute insulin deficiency X X T2DM: insulin resistance insulin resistance is a reduced tissue response to insulin • insulin resistance is linked to excess adipose tissue (overweight) •

Diabetes complications (both T1DM and T2DM): disorders resulting from chronic hyperglycemia cardiovascular disease (heart attack, stroke, peripheral vascular disease) • nephropathy (kidney failure) • retinopathy (blindness) • peripheral neuropathy (loss of sensation; autonomic dysfunction) • foot ulcers (amputation) • Diabetic ketoacidosis: acute crisis due to lack of insulin hyperglycemia, high ketones • acidosis • dangerous fluid loss • occurs mainly in T1DM •

Diagnosis of diabetes mellitus a. glycated hemoglobin (HbA1c or A1c) • does not require fasting • glycation: nonenzymatic glycosylation oral glucose tolerance test • glycated hemoglobin reflects amount of hyperglycemia in previous 8 weeks • used both for diagnosis and to measure glycemic control b. fasting plasma glucose • plasma glucose measured after no caloric intake for at least 8 hours c. oral glucose tolerance test (OGTT) • fasting individual ingests 75g glucose and plasma glucose levels are periodically measured for 2 hours fasting plasma Adapted from Figure 22.19a, p. 715 glucose

Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults Obesity (BMI ≥ 30 kg/m 2 ) 1994 2000 2015 No Data <14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% > 26.0% Diabetes 1994 2000 2015 No Data <4.5% 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% >9.0% CDC’s Division of Diabetes Translation. United States Surveillance System available at http://www.cdc.gov/diabetes/data

Summary: treatments for diabetes mellitus insulin metformin sulfonylureas and meglitinides drugs that increase GLP-1 agonists insulin secretion DPP-4 inhibitors SGLT2 inhibitors

In T1DM, the feedback loop is broken injections injected insulin is not perfectly linked to • with functioning beta cells, • plasma glucose level as it is when there insulin secretion is matched to is a closed loop negative feedback loop plasma glucose levels frequent periods of hyperglycemia • risk of hypoglycemia from too much • insulin Treatment strategy: pump linked to continuous glucose monitor to recreate closed loop negative feedback loop

Metformin first drug of choice to treat newly diagnosed diabetes mellitus • also used to treat prediabetes • generic; inexpensive • oral drug • • mechanism of action ??? effects à • improves insulin sensitivity decreases hepatic glucose production promotes weight loss

Insulin resistance means more insulin needed to achieve the same effect (relative insulin deficiency) X T2DM: insulin resistance early response to insulin resistance: hypersecretion of insulin to compensate later: beta cells fail to compensate

Mechanism of insulin secretion What happens to the membrane potential when a K + channel closes? What is the gating factor for these Ca ++ channels? facilitated diffusion: depends on what? pancreatic beta cell Figure 5.26b, p. 158

Mechanism of action of sulfonylurea and meglitinide drugs: increase insulin secretion drugs close K ATP channel K ATP channel closed by drug so does not depend on plasma glucose concentration these drugs also tend risk of hypoglycemia to cause weight gain

Incretins • GLP-1 and GIP • endocrine cells in small intestine epithelium • secretion stimulated by glucose, fats in small intestine • increase glucose-dependent insulin secretion

Secretion and Action of Incretins incretins: GIP, GLP-1

Incretin hormones provide feedforward stimulation of insulin secretion

Incretin-based drugs for the treatment of type 2 diabetes mellitus • GLP-1 agonists (e.g. exenatide, liraglutide) peptides; must be injected more effect on glycemic control promote weight loss • DPP-4 inhibitors (e.g. sitagliptin, linagliptin) � gliptins � ; oral drugs pen injector for liraglutide

Glucose reabsorption in the kidney The nephron is the functional unit of the kidney reabsorption: substances in the forming urine transported back into the ECF Fig.19.1e (pp. 591)

Proteins involved in glucose reabsorption in the kidney SGLT2: sodium-glucose cotransporter specific to kidney

SGLT2 Inhibitors “-gliflozins” (e.g. canagliflozin, dapagliflozin) • oral drugs • promote weight loss • beneficial effects on cardiovascular outcomes; progression of • chronic kidney disease risk of genitourinary infections; ketoacidosis (rare) • top prescribed SGLT2 inhibitors

Treatments for diabetes mellitus: other considerations

Patient F What is glycated hemoglobin? What would be the level of glycated hemoglobin in someone who doesn’t have diabetes? Would you say that Agnes’ diabetes is under control?

What effect do sulfonylurea drugs have that improves glycemic control? Why does this drug cause hypoglycemia?

Questions about incretin-based therapies (GLP-1 agonists; DPP-4 inhbitors): Incretin-based therapies increase insulin secretion. Why is there less risk of hypoglycemia? GLP-1 agonists are similar in structure to native GLP-1 so that they bind and activate the GLP-1 receptor? How do DPP-4 inhibitors work? Agnes has had trouble losing weight, and GLP-1 agonist drugs have been shown to help patients lose weight. Why might a DPP-4 inhibitor be a better choice for Agnes?

What type of protein is SGLT2? Do you think an SGLT2 inhibitor would promote weight gain or weight loss?

Table 22.4, p. 718; drugs discussed in text starting on p.717