What’s the connection between severe hypoglycemia and hypothermia?

The association of severe hypoglycemia and low body temperatures has been well documented at least since 1960s.  Hypothermia is thought to be caused by low blood glucose in the brain (neuroglucopenia) which may serve as a protective mechanism for decreasing energy demand during glucose deprivation.1-2

A 2012 retrospective study involving mostly patients with diabetes mellitus with severe hypoglycemia (majority with serum glucose 18-54 mg/dl) found that 23% of patients had hypothermia (defined as body temperature < 95◦F or 35◦C). The incidence of hypothermia was not affected by age, diabetes, season or time of day.  Two patients had extremely low temperatures (<90◦F).  There was an association between hypothermia and severity of hypoglycemia.1

An older experimental study (1974) involving 36 recumbent nude men in thermoneutral environment found that that insulin-induced hypoglycemia was associated with rectal temperatures below 96.2◦F (36◦C) in 33%.  Cooling was attributed to reduction in heat production and to secretion of sweat, peripheral vasodilatation and hyperventilation.2

But before you attribute hypothermia to hypoglycemia, make sure other causes of hypothermia such as sepsis, hypoadrenalism, hypothyroidism, alcohol and stroke are ruled out.3  

Bonus Pearl: Did you know that heat production is accomplished by shivering, which can increase the normal basal metabolic rate by 2-5 times as well as via non-shivering thermogenesis through increased levels of thyroxine and epinephrine?3

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References

  1. Tran C, Gariani K, Hermann FR, et al. Hypothermia is a frequent sign of severe hypoglycaemia in patients with diabetes. Diab Metab 2012;38:370-72. https://www.sciencedirect.com/science/article/abs/pii/S1262363612000535?via%3Dihub
  2. Strauch BS, Felig P, Baxter JD, et al. Hypothermia in hypoglycemia. JAMA 1969;210:345-46. https://jamanetwork.com/journals/jama/article-abstract/349081
  3. McCullough L, Arora S. Diagnosis and treatment of hypothermia. Am Fam Physician 2004;70:2325-2332. https://www.aafp.org/afp/2004/1215/p2325.html

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the connection between severe hypoglycemia and hypothermia?

Is there a connection between trehalose, a natural sugar found in many foods, and Clostridioides difficile disease (CDD)?

There is experimental and epidemiological evidence that trehalose in the diet may enhance the virulence of the epidemic strains (eg. Ribotype 027) of C. difficile (1). 
Many of us may not be familiar with trehalose. It’s a disaccharide composed of 2 glucose molecules and found widely in nature, including bacteria, fungi (eg mushrooms, Brewer’s yeast), plants, insects, other invertebrates, but not vertebrates (2).

Since its approval by the FDA as a natural food additive in 2000, trehalose is increasingly used for its unique properties (including flavor enhancer and moisture stabilizer) in a variety of foods, including ice cream, pasta, ground beef, and sushi. Although in humans trehalose is enzymatically broken down to glucose by the brush borders of intestinal mucosa, intact trehalose is also found in the lower GI tract where C. difficile thrives.
In a series of intriguing experiments involving the interaction between trehulose and C. difficile published in Nature in 2018, Collins et al found that RT027 strain of C. difficile had acquired unique mechanisms to metabolize low concentrations of trehalose and that dietary trehalose increased its virulence associated with high mortality in a mouse model of infection even in the absence of antibiotic exposure. They further demonstrated that when human diet was simulated (eg, at concentrations suggested in ice cream), trehalose levels in the cecum of the mice were sufficient to induce production of the enzyme phosphotrehalase by the same strain in vitro by over 400X in the absence of antibiotics and by over 1000X in the presence of antibiotics. Similar results were found in the ileostomy fluid samples of 2 of 3 volunteers consuming normal diet (1). 
Equally fascinating is the epidemiological evidence that the timelines of trehalose adoption as a food additive in 2000, subsequent uptick in the number CDDs in the US, as well as the spread of RT027 strain in many countries seem to overlap (1).

 
These observations may at least partially explain the frequently severe nature of CDD during the past 2 decades as well why a significant proportion (up to a-third) of patient with CDD appear to have no recent exposure to antibiotics or hospitalization (3-5).  An epidemiological study examining the dietary habits of patients with CDD without apparent risk factors is in order. Stay tuned!
Bonus Pearl: Did you know that trehalose is classified as “generally regarded as safe” (GRAS)  natural food additive by the FDA and may be listed as “added sugar” or “natural flavor” on the food packaging?

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References
1. Collins J, Robinson C, Danhof H, et al. Dietary trehalose enhances virulence of epidemic Clostridium difficile. Nature 2018;553;291-96. https://www.nature.com/articles/nature25178
2. Avonce N, Mendoza-Vargas A, Morett E, et al. Insights on the evolution of trehalose biosynthesis. BMC Evol Biol 2006;6:109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769515/
3. Wilcox MH, Mooney L, Bendall R, Settle CD et al. A case-control study of community-associated Clostridium difficile infection. J Antimicrob Chemother 2008;62:388-96. https://www.researchgate.net/publication/5419268_A_case-control_study_of_community-associated_Clostridium_difficile_infection
4. Severe Clostridium difficile-associated disease in populations previously at low risk. MMWR2005;54:1201-5. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5447a1.htm
5. Halvorson SAC, Cedfeldt AS, Hunter AJ. Fulminant, non-antibiotic associated Clostridium difficile colitis following Salmonella gastroenteritis. J Gen Intern Med 2010;26:95-7.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Is there a connection between trehalose, a natural sugar found in many foods, and Clostridioides difficile disease (CDD)?