A Human Randomized Controlled Trial Comparing Metabolic Responses to Single and Repeated Hypoglycemia in Type 1 Diabetes

Abstract

Aims Hypoglycemia hinders optimal glycemic management in type 1 diabetes (T1D). Long diabetes duration and hypoglycemia impair hormonal counterregulatory responses to hypoglycemia. Our study was designed to test whether i) the metabolic responses and insulin sensitivity are impaired, and ii) affected by short-lived antecedent hypoglycemia in participants with T1D. Materials and Methods In a randomized, crossover, 2x2-factorial design, nine male participants with T1D and nine comparable control participants underwent 30 min hypoglycemia (p-glucose<2.9mmol/L) followed by a euglycemic clamp on two separate interventions: with and without 30 min hypoglycemia the day before the study day. Results During both interventions: insulin sensitivity was consistently lower, while counterregulatory hormones were reduced with 75% lower glucagon and 50% lower epinephrine during hypoglycemia in participants with T1D, who also displayed 40% lower lactate and 5-10-fold increased ketone bodies concentrations following hypoglycemia, whereas palmitate and glucose turnover, forearm glucose uptake and substrate oxidation did not differ between the groups. In participants with T1D, adipose tissue PTEN content, HSL phosphorylation and muscle GLUT4 content were decreased compared with controls. An antecedent hypoglycemic episodes lasting 30 minutes did not affect counter-regulation or insulin sensitivity. Conclusions Participants with T1D displayed insulin resistance, and impaired hormonal counter-regulation during hypoglycemia, whereas glucose and fatty acid fluxes were intact, and ketogenic responses amplified. We observed subtle alterations of intracellular signaling, and no effect of short-lived antecedent hypoglycemia on subsequent counter-regulation. This plausibly reflects the presence of insulin resistance, and implies that T1D is a condition with defective hormonal but preserved metabolic responsiveness to short-lived hypoglycemia.

Mini‐review: Glucagon responses in type 1 diabetes – a matter of complexity

“…Originally reported by Gerich et al in 1973 (Gerich et al, 1973), the lack of any glucagon counter regulatory response to hypoglycemia has consistently been confirmed in individuals with type 1 diabetes (Bengtsen et al, 2020;Cryer et al, 2001). In the past, long diabetes duration was considered a prerequisite for the lack of glucagon response to occur but mounting evidence suggest that it often occurs as early as the first months to years after the diagnosis of type 1 diabetes (Siafarikas et al, 2012).…”

“…It has been known for several years that systemic infection and inflammation is associated with high circulating concentrations of glucagon (Rocha et al, F I G U R E 2 Glucagon response (pg/ml) to specific stimuli in type 1 diabetes. Hypoglycemia (Hypo) (Bengtsen et al, 2020;Gerich et al, 1973) does not elicit a glucagon responses in individuals with type 1 diabetes whereas exercise (Mallad et al, 2015), insulin withdrawal (Moller et al, 2006;Voss et al, 2018) and insulin withdrawal combined with lipopolysaccharide administration (insulin withdrawal +LPS) (Svart et al, 2016) lead to profound glucagon responses. The paradoxical glucagon increase following a meal is evidenced by an oral glucose tolerance test with 50 gram glucose (OGGT 50g) (Hare et al, 2010) and by orally administered 40 gram alanine (AA oral 40g ala) (Wiethop & Cryer, 1993) or 42 gram mixture of amino acids (AA oral 42g mixture) (Rosetti et al, 2008).…”

“…This paper is inspired by a series of human randomized, controlled trials from 2014 to 2019 conducted at our research facility at the Department of Endocrinology and Internal Medicine, Aarhus University Hospital in Denmark. All four studies (Bengtsen et al, 2020;Rittig et al, 2015;Svart et al, 2016;Voss et al, 2018) and all data including glucagon samples have previously been published.…”

“…Glucagon is recognized as a counter regulatory hormone released during stress conditions, such as hypoglycemia, exercise, systemic inflammation and fasting (Finan et al, 2020;Walker et al, 2011). It is well established that glucagon responses to hypoglycemia are severely impaired in type 1 diabetes (Bengtsen et al, 2020;Cryer et al, 2001;Gerich et al, 1973) but whether glucagon secretion is completely intact following other physiological and metabolic stressful stimuli compared with nondiabetic individuals has been less thoroughly investigated. The aim of this mini-review was to: (i) summarize the current knowledge on glucagon responses during hypoglycemia in normal physiology and type 1 diabetes, and (ii) review human in vivo studies investigating glucagon responses during various stressful conditions in individuals with type 1 diabetes compared with the physiological response in nondiabetic individuals.…”

“…The aim of this mini-review was to: (i) summarize the current knowledge on glucagon responses during hypoglycemia in normal physiology and type 1 diabetes, and (ii) review human in vivo studies investigating glucagon responses during various stressful conditions in individuals with type 1 diabetes compared with the physiological response in nondiabetic individuals. The current review is prompted by a series of human trial conducted at our research facility (Bengtsen et al, 2020;Rittig et al, 2015;Svart et al, 2016;Voss et al, 2018), and all data have previously been published.…”