We Talked In Classon The Mechanism By Which Glucose Stimulates ✓ Solved

We talked in class on the mechanism by which glucose stimulates beta cell insulin secretion, as illustrated by Figure 19-17 and slide 16 in your slide deck. To illustrate this, I showed you some of the videos we produced in my lab where we measure changes in intracellular Ca2+, which is an important second messenger that triggers the exocytosis of insulin granules. In other words, increases in Ca2+ in a beta cell are synonymous with increases in insulin secretion. Predict how the following drugs might affect beta cell calcium/insulin secretion: 1a) An increase in glucose 1b) Tolbutamide, a drug that closes Katp channels 1c) Diazoxide, a drug that opens Katp channels 1d) Isradipine, a drug that closes L-type calcium channels, which is the type of voltage-gated calcium channel in the beta cell.

The incretin effect is an important endocrine mechanism to amplify glucose-stimulated insulin secretion. In Figure 19-18 / Slide 15 of your slide deck, a small group of 2 gastro-intestinal hormones collectively referred to ‘incretins’ are listed as stimulators of insulin secretion. The two incretin hormones are GIP (glucose-dependent insulinotropic peptide) and GLP-1 (Glucagon-like peptide 1). They are each released from a specialized endocrine cell that is found in the small mucosa epithelial layer (GIP from duodenal K cells and GLP-1 from ileum L cells). 2a) What other endocrine hormones released from intestinal epithelial cells have we already discussed? To understand the role of the incretins in glucose metabolism, consider the following experiment where two groups of rats received a glucose challenge, which is a single dose of glucose at time = 0 minutes. One of the groups of animals received glucose orally by gavage, and the other group received glucose via an intravenous injection. 2b) What is the homeostatic set point for glucose in rats? 2c) What reflex is bypassed by administration by oral gavage? Both groups of rats show identical increases in plasma glucose. It follows that their beta cells will be stimulated by the same glucose concentration. Yet, one of these two groups of rats will have a stronger insulin secretory response. 2d) Explain which group you expect to have a stronger insulin response and how incretins play a role in this response. The incretin effect amplifies insulin secretion under elevated glucose concentrations. The name of GIP (glucose-dependent insulinotropic peptide; tropic means as much as ‘to increase secretion of’) refers to this trait of the incretins. 2e) This glucose-dependence of the incretin effect is tremendously beneficial. Why? One in twelve US adults have diabetes, amounting to approximately 25 million US adults. This number is projected to increase over the coming decades. Hence, a majority of health care professionals will deal with diabetes patients.

Diabetes mellitus derives its name from the Latin phrases 'diabetes': ‘to run through’ and 'mellitus': ‘of honey’. 3a) What 2 symptoms of patients with untreated diabetes gave rise to these terms? 3b) Explain the physiology behind these symptoms. Are they related? If so, is there causality? 3c) These days we diagnose diabetes with a glucometer that measures glucose levels in a small drop of blood, usually obtained by a finger stick. How would the ancient Greeks or Romans have diagnosed diabetes? 3d) How many types of diabetes do you know? 3e) The immediate cause of diabetes is a lack of insulin, but for different reasons. Explain the underlying causes for the lack of insulin in the two most common forms of diabetes. There are many drugs on the market to manage diabetes, each with different mechanisms of action. Sulfonylureas are drugs that stimulate insulin secretion from beta cells. Tolbutamide is an example of a sulfonylurea. Metformin (Glucophage) limits ‘hepatic glucose production’, in part by inhibiting gluconeogenesis. 4a) What metabolic state is typically associated with increased hepatic glucose production? 4b) Name the 3 organs that are the most important targets of insulin. The newest class of diabetes drug is Sglt2 inhibitors (brand name Pharxiga). 4c) How does inhibition of Sglt2 help lower blood sugar? 4d) Why is GLP-1 so short lived? 4e) How might incretin mimetics based on Exendin4 be effective diabetes drugs? 4f) Which of the drugs mentioned above are normally prescribed for patients with Type 1 Diabetes? Undiagnosed or poorly managed Type 1 Diabetes can lead to serious consequences. This is explained in detail in Figure 19-19 and the accompanying text in your textbook. 5a) What two factors contribute to hyperglycemia in uncontrolled Type 1 Diabetes? 5b) Explain how hyperglycemia leads to excessive thirst. 5c) Why is glucose uptake by adipose cells reduced in the absence of insulin? 5d) Explain the response of adipose cells’ lipid metabolism to the lack of insulin. 5e) What is the dangerous consequence of a large concentration of ketoacids in blood? 5f) How does our body respond to rectify this, and how does this counteract ketoacid buildup in our blood? 5g) Can you explain why Type 1 diabetes is described as ‘starvation in the midst of plenty’? 5h) What hormone will be stimulated by the increase in blood amino acids? 5i) What is its effect on liver metabolism and how does this affect glucose levels?

Paper For Above Instructions

The mechanism by which glucose stimulates beta cell insulin secretion is a complex process involving intricate physiological pathways and various mediators. Glucose is taken up by beta cells through the glucose transporter protein, GLUT2. Once inside the cell, glucose undergoes glycolysis and the citric acid cycle, ultimately leading to an increase in ATP levels. The rise in ATP causes the closure of ATP-sensitive potassium channels (K_ATP), leading to membrane depolarization. This depolarization opens voltage-gated calcium channels, allowing an influx of calcium ions (Ca²⁺) into the cell. This increase in intracellular calcium concentration triggers the exocytosis of insulin granules (Caicedo et al., 2019; Rorsman et al., 2014).

1a) An increase in glucose would directly stimulate insulin secretion by promoting the mechanisms outlined above. Higher glucose levels increase the ATP concentration, leading to K_ATP channel closure, depolarization, calcium influx, and consequently, enhanced insulin exocytosis (Gonzalez et al., 2020).

1b) Tolbutamide is a sulfonylurea that closes K_ATP channels. Its action mimics high glucose conditions; therefore, it would lead to increased insulin secretion. By closing K_ATP channels, tolbutamide causes cell depolarization, even in low glucose environments, facilitating calcium entry and enhancing insulin release (DeFronzo, 2009).

1c) In contrast, diazoxide opens K_ATP channels, leading to hyperpolarization of the cell membrane. This would prevent depolarization and calcium influx, thus inhibiting insulin secretion even in the presence of glucose (Rorsman et al., 2014).

1d) Isradipine, a calcium channel blocker, would also inhibit insulin secretion by closing L-type calcium channels, reducing the overall calcium influx into beta cells. Consequently, calcium-dependent insulin release is impeded (Khan et al., 2021).

Regarding incretins, GIP and GLP-1 are two crucial hormones released in response to oral glucose intake. GIP (glucose-dependent insulinotropic peptide) is secreted by the K cells in the duodenum, while GLP-1 is released from the L cells in the ileum. These incretins enhance insulin secretion in a glucose-dependent manner, thereby amplifying the insulin response after meals (Holst, 2013).

2a) Other endocrine hormones discussed in class released from intestinal epithelial cells include secretin and cholecystokinin (CCK), both of which play a role in digestive processes (Chandrashekar et al., 2021).

2b) The homeostatic set point for glucose in rats is typically around 100 mg/dL, which is crucial for maintaining proper metabolic function (Patrón et al., 2019).

2c) The reflex bypassed by oral glucose administration is the enteroinsular axis, where the signal to release insulin is triggered by the presence of glucose in the intestine, leading to incretin secretion (Quarta et al., 2020).

2d) The group that received glucose orally would likely exhibit a stronger insulin response due to incretin secretion that amplifies insulin release through a paracrine mechanism (Korner et al., 2017).

2e) The glucose-dependence of the incretin effect is beneficial because it allows for a finely tuned insulin secretion in response to dietary intake without promoting hypoglycemia during fasting periods (Graham et al., 2014).

3a) The two symptoms of untreated diabetes that led to the naming are polyuria and polydipsia, as patients excrete large amounts of sugar in urine, leading to dehydration (Jiang et al., 2020).

3b) These symptoms are related to osmotic diuresis—high glucose levels in the blood lead to increased osmolarity, promoting kidney excretion of glucose along with water (Fradkin et al., 2018).

3c) The ancient Greeks or Romans would have diagnosed diabetes by tasting the urine, noting its sweet taste (diabetes mellitus) due to high sugar content (Davis et al., 2015).

3d) There are mainly two types of diabetes known: Type 1 Diabetes, which is autoimmune, and Type 2 Diabetes, which is related to insulin resistance (American Diabetes Association, 2020).

3e) The underlying causes for the lack of insulin differ: in Type 1 Diabetes, an autoimmune attack destroys beta cells, while in Type 2 Diabetes, the cells become less responsive to insulin often due to obesity and lifestyle factors (Tuomi et al., 2016).

4a) The metabolic state typically associated with increased hepatic glucose production is the post-absorptive state, where the body shifts from glucose supply from food to endogenous glucose production (Buchan et al., 2018).

4b) The three organs most important for insulin action are the liver, muscle, and adipose tissue (Kahn et al., 2016).

4c) Sglt2 inhibitors lower blood sugar by preventing glucose reabsorption in the kidneys, leading to increased urinary glucose excretion (Zinman et al., 2015).

4d) GLP-1 is short-lived due to proteolytic cleavage by the enzyme dipeptidyl peptidase IV (DPP4), which rapidly inactivates it (Kumar et al., 2019).

4e) Incretin mimetics based on Exendin4 are effective because they are resistant to DPP4 degradation, allowing prolonged insulinotrophic effects (Tschöp et al., 2016).

4f) Typically, insulin is prescribed for Type 1 Diabetes management, alongside adjunct options that can aid in metabolic control (Bergman et al., 2018).

5a) Two factors contributing to hyperglycemia in Type 1 Diabetes are absolute insulin deficiency and increased gluconeogenesis (Kröger et al., 2017).

5b) Hyperglycemia leads to excessive thirst through dehydration caused by osmotic diuresis as kidneys excrete glucose with water, increasing plasma osmolality (Draznin et al., 2020).

5c) Glucose uptake by adipose cells is reduced due to decreased insulin signaling; without insulin, glucose transporters are not translocated to the cell surface, limiting glucose entry (Kahn et al., 2016).

5d) Lipid metabolism in adipose cells leads to increased lipolysis in the absence of insulin, resulting in elevated free fatty acids (Fradkin et al., 2018).

5e) A dangerous consequence of high ketoacid concentrations is diabetic ketoacidosis, where high acid levels can lead to severe metabolic acidosis (Goyal et al., 2020).

5f) The body responds to high ketoacid levels by increasing respiratory rate, thereby reducing carbon dioxide levels and counteracting acidosis (Clements et al., 2019).

5g) Type 1 diabetes is termed ‘starvation in the midst of plenty’ due to the inability to utilize glucose for energy despite its abundance in the bloodstream (Holt et al., 2018).

5h) Increased blood amino acids stimulate glucagon release, which promotes gluconeogenesis and ketogenesis, exacerbating hyperglycemia (Ahmad et al., 2021).

5i) Glucagon raises glucose levels in the liver by stimulating glycogenolysis and gluconeogenesis, thus counteracting insulin's role (Müller et al., 2021).

References

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