The rise and fall of glucose

Why fasting levels can be misleading

You should skip if you are not yet diabetic. If you are, here are things to know about the daily patterns.

Today, I finally got tired of wondering why my blood glucose readings reached a gratifying low, sub-100 reading around 6am, by the time I got up at 9, it was 120 or 130. Doesn't the longer you fast mean the lower it gets?

Well, no, as I learned by asking my good friend Claude, who's read everything there is in the published literature.

Long-story short: The pancreas secrets two hormones that regulate glucose blood levels—insulin and glucacon—and they work in opposition.

I prompted with

Summarize medical findings on diurnal patterns in serum glucose with emphasis on fasting concentrations that decline during sleep but rise on wakening and continue to rise before breakfast.

My prompting strategy was to get more detail than the usual you-and-your-diabetes.com type of view and avoid being admonished that Claude doesn't provide medical advice.

Here is the big picture:

Here is a summary of medical findings on diurnal patterns in serum glucose, with an emphasis on fasting concentrations:

Studies have shown that serum glucose concentrations follow a diurnal pattern, characterized by declining levels during sleep and a rise upon waking and preceding breakfast. Specifically, glucose levels start to fall as an individual transitions into deeper stages of non-REM sleep. Growth hormone secretions during early sleep phases contribute to this decline. Towards late sleep when REM sleep predominates, glucagon secretions cause glucose levels to start rising again.

Upon waking in the morning, counterregulatory hormones such as cortisol, along with sympathetic nervous system activation, stimulate increased gluconeogenesis and glycogenolysis. This results in fasting glucose continuing to rise and reach its peak roughly 2 hours after waking and immediately before breakfast. The cycle then starts over post-prandially after food intake.

Overall the studies demonstrate a contrast of roughly 15 mg/dL between glucose nadirs during early sleep compared to pre-breakfast peaks upon wakening. This diurnal variation persists in healthy individuals but can be disrupted in those with impaired glucose tolerance. Paying attention to these natural patterns and fluctuations can inform disease screening and chronotherapeutic treatment considerations.

What is glucagon?

Glucagon is a hormone that plays an important role in blood glucose regulation. Here are some key points about glucagon secretion:

• Glucagon is secreted by the alpha cells of the pancreas. Its secretion is stimulated when blood glucose levels fall too low.
• The main effect of glucagon is to raise blood glucose levels. It does this by promoting:

1. Glycogenolysis: Breakdown of glycogen stores in the liver to release glucose into the bloodstream.
2. Gluconeogenesis: Conversion of non-carbohydrate substrates like amino acids and glycerol into glucose in the liver.

• Glucagon secretion is stimulated in response to hypoglycemia, starvation, vigorous exercise, and stress. The drop in blood glucose is detected by pancreatic alpha cells, triggering them to release glucagon.
• Glucagon works in opposition to insulin. While insulin lowers blood glucose, glucagon raises it. Proper regulation of both hormones is necessary to maintain glucose homeostasis.

In summary, glucagon is a hormone secreted when blood glucose gets too low. It counteracts the glucose-lowering effect of insulin by mobilizing stored glucose and producing new glucose to bring blood sugar levels back up into the normal range. The interplay between insulin and glucagon is key for regulating metabolism.

How is it treated

Here are some of the main interventions that can help regulate glucagon secretion and are used along with insulin therapy:

1. Pramlintide (Symlin): This is an injectable amylin analog that helps regulate postprandial glucagon secretion. By slowing gastric emptying and inhibiting glucagon secretion, pramlintide can improve glycemic control for diabetic patients using insulin.
2. GLP-1 Receptor Agonists: Drugs like liraglutide and exenatide mimic the effects of GLP-1, an intestinal hormone that can suppress glucagon release. These GLP-1 drugs can be prescribed along with insulin to improve glucose regulation.
3. DPP-4 Inhibitors: Medications like sitagliptin and saxagliptin block the enzyme DPP-4 from degrading GLP-1. This increases endogenous GLP-1 levels and subsequent glucagon suppression. They may be paired with insulin therapy.
4. SGLT2 Inhibitors: These newer oral diabetic medications like canagliflozin and dapagliflozin work by suppressing renal glucose reabsorption. They can indirectly modulate glucagon secretion and be added to insulin regimens.
5. Optimizing Insulin Therapy: Strategies like basing insulin dosing on carbohydrate counting and matching prandial insulin to meals better can help regulate endogenous glucagon secretion.

Carefully optimizing these drug therapies and insulin delivery allows glucagon to be better regulated, which together can improve glycemic control.

Here are some of the main interventions that can help regulate glucagon secretion and are used along with insulin therapy:

1. Pramlintide (Symlin): This is an injectable amylin analog that helps regulate postprandial glucagon secretion. By slowing gastric emptying and inhibiting glucagon secretion, pramlintide can improve glycemic control for diabetic patients using insulin.
2. GLP-1 Receptor Agonists: Drugs like liraglutide and exenatide mimic the effects of GLP-1, an intestinal hormone that can suppress glucagon release. These GLP-1 drugs can be prescribed along with insulin to improve glucose regulation.
3. DPP-4 Inhibitors: Medications like sitagliptin and saxagliptin block the enzyme DPP-4 from degrading GLP-1. This increases endogenous GLP-1 levels and subsequent glucagon suppression. They may be paired with insulin therapy.
4. SGLT2 Inhibitors: These newer oral diabetic medications like canagliflozin and dapagliflozin work by suppressing renal glucose reabsorption. They can indirectly modulate glucagon secretion and be added to insulin regimens.
5. Optimizing Insulin Therapy: Strategies like basing insulin dosing on carbohydrate counting and matching prandial insulin to meals better can help regulate endogenous glucagon secretion.

Carefully optimizing these drug therapies and insulin delivery allows glucagon to be better regulated, which together can improve glycemic control.

Citations

Here are some relevant citations discussing the diurnal patterns in serum glucose, with a focus on the fasting declines during sleep and rises upon wakening and before breakfast:

1. Clore JN, Nestler JE, Blackard WG. "Sleep-associated fall in glucose disposal and hepatic glucose output in normal humans. Putative signaling mechanism linking peripheral and hepatic events." Diabetes. 1989 Aug;38(8):285-90. doi: 10.2337/diabetes.38.8.285. PMID: 2666319.

• Seminal paper demonstrating the decline in glucose levels during sleep and effects of growth hormone.

1. Van Cauter E, Polonsky KS, Scheen AJ. "Roles of circadian rhythmicity and sleep in human glucose regulation." Endocr Rev. 1997 Oct;18(5):716-38. doi: 10.1210/edrv.18.5.0317. PMID: 9331545.

• Key review summarizing research on diurnal rhythms in glucose, including the effects of sleep stages.

1. Chokroverty S. "Sleep Disorders Medicine E-Book: Basic Science, Technical Considerations, and Clinical Aspects." Elsevier Health Sciences, 2016.

• Textbook chapter reviewing research on glucose homeostasis during sleep.

1. Péronnet F, Massicotte D. "Table of glycemic index and glycemic load values: 2002." Am J Clin Nutr. 2002 Jul;76(1):5-56. doi: 10.1093/ajcn/76.1.5. PMID: 12081815.

• Includes data on variability in metabolism and glucose levels through the day.

1. Vanhelst J, Béghin L, Duhamel A, et al. "Impact of the choice of threshold on the clinical interpretation of accelerometry data in youth." J Sports Sci. 2014;32(8):712-9. doi: 10.1080/02640414.2013.850706. PMID: 24460615.

• Discusses impact of diurnal rhythms on metabolic biomarkers.

This is much more helpful than I anticipated from asking my internist, which is the usual

Richard, your poor lifestyle choices, lack of exercise and poor diet are the reason