Diabetes worksheet

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

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1b) Tolbutamide, a drug that closes Katp channels

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1c) Diazoxide, a drug that opens Katp channels

Answer

 

1d) Isradipine, a drug that closes L-type calcium channels, which is the type of voltage-gated calcium channel in the beta cell.

Answer

 

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?

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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, the other group received glucose via an intravenous injection.

2b) What is the homeostatic set point for glucose in rats?

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2c) What reflex is bypassed by administration by oral gavage?

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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.

Answer

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?

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One in twelve US adults have diabetes. This amounts to approximately 25 million US adults, a number that is projected to increase starkly over the coming decades. This means that a majority of physicians, nurse practitioners and other health care professionals will deal with patients that have diabetes, either as the primary indication or as a co-morbidity in a patient that is admitted or referred for other indications. With between 400 and 500 students enrolled in NPB101, it is likely that some of you have diabetes, and many more of you will have relatives with diabetes.

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.

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3b) Explain the physiology behind these symptoms. Are they related? If so, is there causality?

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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?

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3d) How many types of diabetes do you know?

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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.

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There are a number of drugs on the market to manage diabetes. They have different mechanisms of action. Here are a few with a short description of how they work.

Sulfonylureas are drugs that stimulate insulin secretion from beta cells. Tolbutamide is an example of a sulfonylurea, although newer sulfonylureas such as glibenclamide are more commonly used instead.

Metformin (Glucophage) is a drug that is cheap and generally safe and effective. It works to limit ‘hepatic glucose production’, in part by inhibiting gluconeogenesis.

4a) What metabolic state is typically associated with increased hepatic glucose production?

Absorptive state/post-absorptive state

 

Thiazolidinediones (TZDs) improve/restore insulin action, or promote the sensitivity of target cells for insulin.

4b) Almost all cells of our body have insulin receptors and can respond to insulin. However, from a whole body perspective, name the 3 organs that are the most important targets of insulin.

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The newest class of diabetes drug to hit the market are Sglt2 inhibitors (brand name Pharxiga).

4c) How does inhibition of Sglt2 help lower blood sugar?

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The incretin effect is targeted by not one but two classes of diabetes drugs. They both target the mechanism by which endogenous (produced by our own L cells) GLP-1 is degraded. Endogenous GLP-1 is short lived; a molecule of GLP-1 in our blood circulates for about 6 minutes.

4d) Why is GLP-1 so short lived?

Answer

 

Inactivation of GLP-1 is mediated by an enzyme called di-peptidyl-peptidase IV (DPP4). One class of diabetes drugs works by inhibiting DPP4, which inhibits the degradation of GLP-1 and thus prolongs the time over which GLP-1 remains active. Januvia is an example of such a drug.

Exenatide (Byetta) is drug that targets the incretin effect in a different way. These drugs are known as incretin mimetics. They are based on a peptide called Exendin4 that was originally discovered in the saliva of the Gila monster (Heloderma suspectum) a lizard native to the Sonora desert and one of two venomous lizards in North America. This peptide is about 50% identical to our own GLP-1 and it works in much the same way. However, Exendin4 differs from GLP-1 in the region where GLP-1 is cleaved and inactivated by DPP4.

Gila monster - Heloderma suspectum

 

4e) How might this make incretin mimetics based on Exendin4 effective diabetes drugs?

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4f) Which of the drugs mentioned above are normally prescribed for patients with Type 1 Diabetes?

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Undiagnosed or poorly managed Type 1 Diabetes can lead to serious, sometimes fatal consequences. These are explained in detail in Figure 19-19 and explained step by step in the accompanying text in your textbook. While this figure is daunting, it helps if you split the response up by nutrient, starting with carbohydrates, and walk through them step by step.

5a) What two factors contribute to hyperglycemia in uncontrolled Type 1 Diabetes?

Answer

 

Although Type 1 Diabetes can be diagnosed at almost any age, it most commonly is diagnosed in children, with the average age of diagnosis between 10-12 years old. One of the tell-tale signs (although too often missed) is excessive thirst.

 

5b) Explain how hyperglycemia is leading to excessive thirst?

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Insulin is the major absorptive state hormone, and in its absence, the body thinks it is in a fasting state. Adipose (fat) cells are unable to take up glucose in the absence of insulin.

 

5c) Why is glucose uptake by adipose cells reduced?

Answer

 

5d) What would be the response of adipose cells’ lipid metabolism to the lack of insulin?

Triglyceride synthesis is increased/decreased and lipolysis is increased/decreased, which leads to an increase in blood fatty acids.

 

The liver uses the increased fatty acids and converts them into ketone bodies, also known as ketoacids. Ketoacids can be used as cellular fuel source by most cells of the body, except for our CNS. Increased ketosis by the liver essentially spares glucose for our brains to use. Ketoacid levels in most individuals are really low. Someone on a ketogenic diet might have slightly higher levels of ketoacids, but nothing close to what is seen in some patients with undiagnosed diabetes.

 

5e) What is the dangerous consequence of a large concentration of ketoacids in blood?

Answer, use the formal name.

 

5f) How does our body respond to rectify. Explain how this counteracts the consequence of ketoacid buildup in our blood?

Answer

 

In the absence of insulin, amino acid uptake by cells will be reduced and protein degradation will be increased, leading to muscle wasting. Many kids with Type 1 Diabetes struggle to put on weight.

 

5g) Type 1 diabetes has been described as ‘starvation in the midst of plenty’. Can you explain why?

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5h) What hormone will be stimulated by the increase in blood amino acids?

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5i) What is its effect on liver metabolism and how does this affect glucose levels?

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