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

islet of Langerhansàendocrine secretion to bloodstream

to the duodenum

duct cells acinar cells acinar cells and duct cellsàexocrine secretion via ducts to the GI tract

Endocrine vs. exocrine pancreas

Pancreas

islets of Langerhans (pancreatic islets): pale- staining regions

Low magnification view of the pancreas

Pancreas

each dark cluster is an acinus containing acinar cells

High magnification view of the pancreas

(duct cells not visible) pale cells are endocrine (hormone-secreting) cells in the pancreatic islet:

• beta cells: secrete insulin
• alpha cells: secrete glucagon

electron micrograph showing acinar cells with dark zymogen granules and abundant rough ER

Acinar cells secrete inactive enzyme precursors called zymogens

Figure 15.15c from Wheater’s Functional Histology

Role of hormones in endocrine pancreas: regulating metabolism in the fed and fasted states

Figure 22.14a and b, p. 709

• 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

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

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

Diabetes mellitus

Both T1DM and T2DM cause hyperglycemia

X

T1DM: absolute insulin deficiency

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
• ccurs mainly in T1DM

• a. glycated hemoglobin (HbA1c or A1c)
• does not require fasting
• glycation: nonenzymatic glycosylation
• 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

Diagnosis of diabetes mellitus

• ral glucose tolerance test

fasting plasma glucose

Adapted from Figure 22.19a, p. 715

Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults

Obesity (BMI ≥30 kg/m2) Diabetes 1994 1994 2000 2000

No Data <14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% > 26.0% 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

2015 2015

Summary: treatments for diabetes mellitus

insulin metformin sulfonylureas and meglitinides GLP-1 agonists DPP-4 inhibitors SGLT2 inhibitors

drugs that increase insulin secretion

In T1DM, the feedback loop is broken

injections

• injected insulin is not perfectly linked to

plasma glucose level as it is when there is a closed loop negative feedback loop

• frequent periods of hyperglycemia
• risk of hypoglycemia from too much

insulin

• with functioning beta cells,

insulin secretion is matched to plasma glucose levels

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
• ral drug
• mechanism of action ???
• effectsà

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

Figure 5.26b, p. 158

Mechanism of insulin secretion

facilitated diffusion: depends on what? What happens to the membrane potential when a K+ channel closes? What is the gating factor for these Ca++ channels? pancreatic beta cell

drugs close KATP channel KATP channel closed by drug so does not depend on plasma glucose concentration

Mechanism of action of sulfonylurea and meglitinide drugs: increase insulin secretion

risk of hypoglycemia these drugs also tend to cause weight gain

• GLP-1 and GIP
• endocrine cells in small

intestine epithelium

• secretion stimulated by

glucose, fats in small intestine

• increase glucose-dependent

insulin secretion

Incretins

Secretion and Action of Incretins

incretins: GIP, GLP-1

Incretin hormones provide feedforward stimulation

• f insulin secretion

Incretin-based drugs for the treatment

• f 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

The nephron is the functional unit of the kidney

Fig.19.1e (pp. 591)

Glucose reabsorption in the kidney

reabsorption: substances in the forming urine transported back into the ECF

Proteins involved in glucose reabsorption in the kidney

SGLT2: sodium-glucose cotransporter specific to kidney

SGLT2 Inhibitors

• “-gliflozins” (e.g. canagliflozin, dapagliflozin)
• ral 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