New brain pathway offers hope for treating hypogylcemia

For those with diabetes, managing blood sugar is a balancing act - if blood sugar is too high it raises the risk for nerve damage, blindness, kidney failure, and heart trouble, and if too low it can lead to a seizure or unconsciousness.

Now a team of scientists from the United Kingdom and the University of Michigan Comprehensive Diabetes Center has taken a step forward in understanding how the brain senses low glucose levels and trigger the body’s response. The discovery may accelerate work to safely control diabetes.

A novel pathway buried deep within a region of the brain called the parabrachial nucleus produces the brain hormone cholecystokinin (CCK) that acts as a crucial sensor of blood glucose levels. The hormone helps orchestrate responses around the body when levels drop too low, according to the study published in Nature Neuroscience.

“It is remarkable to find that such an incredibly small set of cells in the brain play such an important role in maintaining normal glucose levels,” says study author Lora K. Heisler, Chair of Human Nutrition at the Rowett Institute of Nutrition & Health at the University of Aberdeen.

It’s known that CCK cells in the brain modify things like appetite and anxiety but they had previously been overlooked in relation to blood sugar levels, authors say.

“The discovery of the important function of this brain hormone raises the possibility of using drugs targeting the CCK system to boost defences against hypoglycaemia, the clinical syndrome that results from low blood sugar,” says study author Martin G. Myers, Jr., M.D., Ph.D., the Marilyn H. Vincent Professor in Diabetes Research at the University of Michigan Comprehensive Diabetes Center.

New brain pathway offers hope for treating hypogylcemia The authors worked with an international team or researchers from the University of Cambridge, University of Edinburgh, University of Chicago on the findings published in the journal Nature Neuroscience.

Heisler says the identification of the role played by CCK could be of particular significance to an estimated 20 percent of those with diabetes who suffer side effects of low blood sugar, called hypoclycemia.

What are symptoms of hypoglycemia and how low is too low?

The normal range of glucose in the bloodstream is from 70 to 100 mg/dL when the individual is fasting (that is not immediately after a meal). The body’s biochemical response to hypoglycemia usually starts when sugars are in the high/mid 70’s. At this point, the liver releases its stores and the hormones mentioned above start to activate. In many people, this process occurs without any clinical symptoms. The amount of insulin produced also declines in an attempt to prevent a further drop in glucose.

While there is some degree of variability among people, most will usually develop symptoms suggestive of hypoglycemia when blood glucose levels are lower than 50 mg/dL. The first set of symptoms are called adrenergic (or sympathetic) because they relate to the nervous system’s response to hypoglycemia. Patients may experience any of the following;

  intense hunger,
  palpitations, and
  often have trouble speaking.

In most people, these symptoms are easily recognizable. The vast majority of individuals with diabetes only experience this degree of hypoglycemia if they are on medications or insulin. People (with diabetes or who have insulin resistance) with high circulating levels of insulin who fast or change their diet to lower their carbohydrate intake drastically should also be cautioned. These individuals may also experience modest hypoglycemia.

People being treated for diabetes who experience hypoglycemia may not experience symptoms as easily as people without diabetes. This phenomenon has been referred to as hypoglycemic unawareness. This can be dangerous as blood sugars may approach extremely low levels before any symptoms are perceived.

Anyone who has experienced an episode of hypoglycemia describes a sense of urgency to eat and resolve the symptoms. And, that’s exactly the point of these symptoms. They act as warning signs to tell the body to consume more fuel. At this level, the brain still can access circulating blood glucose for fuel. The symptoms provide a person the opportunity to raise blood glucose levels before the brain is affected.

If a person does not or cannot respond by eating something to raise blood glucose, the levels of glucose continue to drop. With further drops in blood glucose, patients progress to neuro-glyco-penic ranges (meaning that the brain is not getting enough glucose). At this point, symptoms progress to confusion, drowsiness, changes in behavior, coma, and seizure.

“When patients suffer repeated bouts of hypoglycemia they can develop ‘unawareness’ which means they find it difficult to detect symptoms that their blood sugar levels are falling and it is this group particularly that we hope could benefit from our findings in regard to the role played by CCK,” Heisler says.

Further research is now needed to look at how we can target the CCK system as well as they cells upon which CCK acts to prevent or treat hypoglycaemia.

Follow these steps, known as the “Rule of 15” to treat low blood sugar.

  Eat a food or beverage containing 15 grams of carbohydrate (see below). Do not use orange juice. Also, avoid items with fat, such as chocolate bars, because fat can delay the rise of sugar in your blood.
  Retest your blood sugar after 15 minutes. If it is still less than 70 mg/dL, eat another portion of food or beverage containing 15 grams of carbohydrate.
  Recheck your blood sugar in 15 minutes. If it is still less than 70 mg/dL, eat another portion of food or beverage containing 15 grams of carbohydrate. If it is above 70 mg/dl, eat a small snack (i.e. 1/2 turkey sandwich) or eat a meal within the next hour.
  Since your blood sugar may begin to drop after 40 to 60 minutes, test again after one hour to make sure your blood sugar is in the range of 70-115 mg/dl.

Foods with 15 grams of carbohydrate

For dialysis patients, it is recommended to use any one of the following items, containing 15 grams of carbohydrate, to treat low blood sugar:

  3 glucose tablets, or 1 tube glucose gel (available in drugstores)
  1 tablespoon or 3 packets of table sugar?
  1/2 cup apple juice or grape juice (avoid orange juice if you are on a low-potassium diet)?
  7 gummy bear candies
  1/2 cup regular (not diet) Sprite&reg:, ginger ale or 7-Up&reg:
  6 Life-Savers&reg:, or 2 to 4 pieces of hard candy?

If hypoglycemia is an ongoing problem, keep one of these items with you at all times.


New brain pathway offers hope for treating hypogylcemia The study was funded in part by the National Institutes of Health, American Diabetes Association, the Wellcome Trust, Animal Phenotyping Core of the Michigan Diabetes Research Center and the Michigan Nutrition and Obesity Research Center.

Reference: “Leptin-inhibited PBN neurons enhance responses to hypoglycaemia in negative energy balance,” Vol. 17, No. 12., Nature Neuroscience.


Shantell Kirkendoll
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  Nature Neuroscience
  National Institutes of Health, American Diabetes Association, The Wellcome Trust, AnimNational Institutes of Health, American Diabetes Assoal Phenotyping Core of the Michigan Diabetes Research Center and the Michigan Nutrition and Obesity Research Center.

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